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AUC0
Kinds of AUC0 Selected AbstractsThe glucose lowering effect of an oral insulin (Capsulin) during an isoglycaemic clamp study in persons with type 2 diabetesDIABETES OBESITY & METABOLISM, Issue 1 2010S. D. Luzio Aim: Randomized, open, single-centre, two-way crossover study comparing the pharmacokinetic (PK) and pharmacodynamic (PD) properties of subcutaneous (sc) regular human insulin (Actrapid) and oral insulin in a capsule form (Capsulin). Methods: Sixteen persons (12 males) with type 2 diabetes on oral hypoglycaemic agents (OHAs) participated. Mean (s.d.) age 60.2 (5.5) years, BMI 28.3 (3.4) kg/m2, haemoglobin A1c (HbA1c) 7.4% (1.1). Two 6-h isoglycaemic glucose clamp studies were conducted 11 days apart. All subjects received in random order 12U sc Actrapid on one clamp study day and either 150U or 300U Capsulin (Cap) on the other day. Glucose infusion rates (GIRs), plasma insulin and C-peptide concentrations were determined throughout each 6-h isoglycaemic clamp. Between the clamp study days, all patients received 150U Capsulin twice daily, dropping all their standard OHAs apart from metformin. Self-monitored blood glucose (SMBG) levels were taken four times a day between the clamp study days. Results: Administration of either Actrapid or Capsulin (150 and 300U) increased GIRs reaching a maximum values at approximately 280,330 min. Overall values for maximum GIR values were higher for Actrapid than either dose of Capsulin (p < 0.05). The significantly greater systemic insulin concentrations following Actrapid were reflected in the AUC0,6 h (910 ± 270 vs. 472 ± 245 pmol h/L; 950 ± 446 vs. 433 ± 218 pmol h/L; both p < 0.05 for Actrapid vs. 150U Capsulin and 300U Capsulin respectively). No difference was observed between 150U and 300U Capsulin. During the repeat-dosing period, good safety and tolerability were observed with Capsulin, and SMBG levels remained stable. At the poststudy visit, significant falls in HbA1c, weight and triglycerides were observed. Conclusions: Administration of the oral insulin Capsulin preparation demonstrated a significant hypoglycaemic action over a period of 6 h associated with only a small increase in circulating plasma insulin concentrations. [source] CLINICAL STUDY: Effect of saquinavir/ritonavir (1000/100 mg bid) on the pharmacokinetics of methadone in opiate-dependent HIV-negative patients on stable methadone maintenance therapyADDICTION BIOLOGY, Issue 3 2009Candice Jamois ABSTRACT This study was performed to determine the effect of two protease inhibitors, saquinavir (SQV, oral 1000 mg bid) boosted by ritonavir (RTV, oral 100 mg bid), on pharmacokinetics (PK) of methadone in opiate-dependent HIV-negative patients on stable methadone maintenance therapy. This was a two-center, open-label, one-sequence cross-over, multiple-dose study in 13 HIV-negative patients who were on stable methadone therapy (oral, 60,120 mg qd). All patients continued methadone treatment on days 2,15. All patients received SQV/RTV in combination with methadone from days 2,15. PK of methadone was assessed on day 1 (alone) and on day 15 when methadone treatment was combined with SQV/RTV at steady state. Twelve patients completed the study. Median age, body weight and height were 50 years (range: 24,54 years), 80 kg (range: 57,97 kg) and 174 cm (range: 163,189 cm), respectively. All patients were Caucasian, and 11 were smokers. Median methadone dose was 85 mg qd. Geometric mean area under curve of the plasma concentration-time curve over 24 hour dosing interval (AUC0,24 hour) ratio of methadone with and without SQV/RTV was 0.81% (90% confidence interval: 71,91%). There was no significant plasma protein-binding displacement of methadone by SQV/RTV. The combination of SQV/RTV and methadone was well tolerated. There were no clinically significant adverse events or significant changes in laboratory parameters, electrocardiograms or vital signs. The 19% decrease in R-methadone AUC0,24 hour in the presence of SQV/RTV was not clinically relevant. There appears to be no need for methadone dose adjustment when methadone (60,120 mg qd) and SQV/RTV (1000/100 mg bid) are coadministered. [source] Pharmacokinetic,pharmacodynamic study of apomorphine's effect on growth hormone secretion in healthy subjectsFUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 4 2003Guy Aymard Abstract Apomorphine (APO) stimulates growth hormone (GH) release via dopamine D2 receptors (DRD2). There is no specific study assessing the relationship between APO pharmacokinetic (PK) and the pharmacodynamic (PD) response e.g. GH release. The objective of the study is the PK,PD modelling of APO in healthy subjects. This is a randomized crossover study with s.c. administration of 5, 10, and 20 ,g/kg of APO in 18 healthy subjects. APO concentrations were modelled according to both a bi-compartmental model with zero-order absorption and a bi-compartmental model with first-order absorption. PK,PD relationship was modelled in accordance with the Emax Hill equation using plasma concentrations of APO calculated according to the bi-compartmental model with zero-order absorption. Modelled parameters were very similar to the experimental parameters. PK of APO was linear and there was no significant difference between the tested doses for AUC0,, and Cmax (normalised to the dose 1 ,g/kg), t1/2, and t1/2,. These parameters expressed as mean (CV%: SD/mean) were: 17.2 (26.9) ng/mL·min, 0.26 (33.3) ng/mL, 17.1 (54.2) and 45.2 (20.6) min, respectively (n = 53). An anticlockwise hysteresis loop (effect function of APO plasma concentration) appeared for each dose and each subject. The predicted and measured GH concentrations for all subjects and times were similar whatever the dose (P > 0.27). Emax values were 246 (121), 180 (107), 205 (139) ng/mL, respectively, and EC50 were 0.98 (48.1), 1.70 (62.3), 3.67 (65.2) ng/mL, respectively at dose 5, 10, and 20 ,g/kg (P < 10,4). APO and GH concentrations were predicted with good accuracy using bi-compartmental with zero-order absorption PK model and sigmoid Emax PD model, respectively. [source] Determination of enalapril and enalaprilat by enzyme linked immunosorbent assays: application to pharmacokinetic and pharmacodynamic analysisFUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 3 2002Khalid Matalka We have developed two enzyme linked immunosorbent assay (ELISA) methods for determining enalapril and enalaprilat in plasma. In this study, 48 healthy subjects received an oral dose of either 10 or 20 mg of enalapril and plasma concentrations of enalapril and enalaprilat were determined by their specific ELISA methods. These plasma concentrations and blood pressure measurements were applied to evaluate the pharmacokinetic (PK) and pharmacodynamic (PD) parameters of both enalapril and enalaprilat. The enalapril values for the area under the curve (AUC0,,) were 480 ± 216 and 832 ± 325 ngh/mL, maximum plasma concentrations (Cmax) were 310 ± 187 and 481 ± 185 ng/mL, and times required to reach the maximum concentration (tmax) were 1.13 ± 0.22 and 1.09 ± 0.33 h for 10 and 20 mg doses, respectively. The enalaprilat values for AUC0,, were 256 ± 122 and 383 ± 158 ngh/mL, Cmax values were 57 ± 29 and 72.9 ± 33.6 ng/mL and tmax values were 4.28 ± 1.45 and 4.05 ± 01.22 h for 10 and 20 mg doses, respectively. The Cmax values of enalapril were ,10 times higher than those in the literature, which were determined by angiotensin converting enzyme (ACE) inhibition assays following alkaline hydrolysis, but similar to those of enalaprilat. The PD profiles revealed a significant correlation between enalaprilat concentrations in plasma and the decrease in systolic and diastolic blood pressures (r=,0.95 with P < 0.001 and r=,0.95 with P < 0.001), respectively, following a single oral dose of enalapril. These ELISA methods have the advantage of being simple, accurate, sensitive, and do not depend on enalaprilat binding to ACE. Such methods can be used for analysis and kinetic testing of enalapril and enalaprilat in biological fluids. [source] Atazanavir and lopinavir with ritonavir alone or in combination: analysis of pharmacokinetic interaction and predictors of drug exposureHIV MEDICINE, Issue 4 2008S Di Giambenedetto Objectives Studies on the pharmacokinetic interaction between atazanavir and lopinavir with ritonavir (lopinavir/ritonavir) report contradictory results. We aimed to establish the in vivo interaction between these two protease inhibitors as well as the variables influencing drug exposure. Methods Pharmacokinetic parameters were investigated in HIV-infected patients treated with atazanavir 300 mg with ritonavir 100 mg q24h (group A) or lopinavir/ritonavir 400/100 mg q12h (group B) or atazanavir 300 mg q24h with lopinavir/ritonavir 400/100 mg q12h (group C). Patients receiving other concomitant protease inhibitors or non-nucleoside reverse transcriptase inhibitors were excluded. Results In group A (n=10), mean ± standard deviation atazanavir Cmin was 390 ± 460 ng/mL, Cmax 3051 ± 1996 ng/mL and AUC24 29 913 ± 17 686 ng/mL/h. In group B (n=9), lopinavir Cmin was 7562 ± 4292 ng/mL, Cmax 12 944 ± 4838 ng/mL and AUC0,12 122 313 ± 38 225 ng/mL/h. In group C (n=7), atazanavir Cmin was 876 ± 460 ng/mL (P=0.039 vs. group A), Cmax 3421 ± 3399 ng/mL and AUC0,24 65 055 ± 49 843 ng/mL/h (two-sided P>0.05 for each comparison with group A), lopinavir Cmin was 7471 ± 3745 ng/mL, Cmax 10 143 ± 5217 ng/mL and AUC0,12 104 501 ± 43 565 ng/mL/h (P>0.05 for each comparison with group B). When analysing all the groups, including controls from routine clinical practice, higher body mass index was associated with lower atazanavir Cmin and with lower lopinavir Cmax. Atazanavir Cmin showed a correlation with total bilirubin levels. Conclusions Combination with lopinavir/ritonavir provides higher atazanavir Cmin than combination with ritonavir alone, possibly because of an effect of the additional ritonavir dose. Low BMI may be associated with higher drug exposure. [source] Pharmacokinetics of mesalazine pellets in children with inflammatory bowel diseaseINFLAMMATORY BOWEL DISEASES, Issue 5 2004Heleen Wiersma MD Abstract Mesalazine is a first-line drug in pediatric inflammatory bowel disease (IBD), and is customarily used to induce and maintain remission in mild to moderate disease. In children, pharmacokinetic data are scarce, and dosage recommendations are largely extrapolated from studies in adults. Aim of the study was to obtain the pharmacokinetic profile of a new mesalazine pellet formulation in children with ulcerative colitis and Crohn's colitis. A single oral dose of 20 mg/kg mesalazine was administered to 13 patients (age 6,16 years). Serial blood and urine sampling for determination of mesalazine and acetylmesalazine was performed before and during 24 hours following ingestion. Maximum plasma concentration of mesalazine (Cmax) was 1332 ng/mL (geometric mean, geometric coefficient of variation [CV]: 0.57), obtained 3.7 hours (tmax; CV: 0.31) after drug administration. Systemic exposure as determined by area under the plasma concentration-time curve (AUC0,, ) was 8712 ng/ml*h (CV: 0.44). Terminal half-life of elimination of mesalazine was 3.5 hours (t1/2; CV: 1.43). This study presents extensive pharmacokinetic data on mesalazine in children with mild-moderately active ulcerative colitis and Crohn's colitis. In comparison with previous experience in adults, pharmacokinetics of mesalazine administered as pellets appear to be similar in both populations. [source] Disposition and pharmacokinetics of a lubricant contaminant, 2,6-di- tert -butyl 4-nitrophenol, in grafted human skinJOURNAL OF APPLIED TOXICOLOGY, Issue 5 2006Lynn K. Pershing Abstract Disposition and uptake/elimination profiles of topical 2,6-di- t -butyl, 4-nitrophenol (DBNP), the nitrated metabolite of an antioxidant additive of lubricant and hydraulic fluids was quantified in human skin grafted on athymic mice after a single topical 75 µg dose in corn oil. DBNP was quantified throughout the stratum corneum (SC), epidermis (E) and dermis (D) in punch biopsies collected from treated skin 0.5, 1, 2, 4, 8 and 24 h after application. SC samples were harvested from the treated skin with 20 adhesive discs. E and D were generated from the biopsy using a manual sectioning method. Detectable DBNP concentrations were measured in all skin compartments at all time points investigated. The Cmax of DBNP in SC was 1663 ± 602 µg cm,3, and ,30 and ,300 fold greater than the Cmax for E and D, respectively. Tmax occurred at 1.0, 0.5 and 1.0 in the SC, E and D, respectively. Over a 24 h interval (AUC0,24 h) there was 52 and 520 fold more DBNP in the SC than E and D, respectively. The elimination half-life of DBNP was 11 h from the SC and 9 h from both E and D. Thus, DBNP was quickly absorbed into the outermost layer of skin and established a steep concentration profile through human skin. The data are consistent with the vast majority of DBNP remaining on the surface (77%) or within human skin (15%) in vivo with only 0.2% of the DBNP dose quantified in the systemic blood circulation. Copyright © 2006 John Wiley & Sons, Ltd. [source] Role of Gastrointestinal Hormones in Postprandial Reduction of Bone Resorption,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 12 2003Dennis B Henriksen Abstract Collagen type I fragments, reflecting bone resorption, and release of gut hormones were investigated after a meal. Investigations led to a dose escalation study with glucagon like peptide-2 (GLP-2) in postmenopausal women. We found a dose-dependent effect of GLP-2 on the reduction of bone resorption. Introduction: The C-terminal telopeptide region of type I collagen as measured in serum (s-CTX) can be used to assess bone resorption. This marker of bone resorption has a significant circadian variation that is influenced by food intake. However, the mediator of this variation has not been identified. Materials and Methods: We studied the release of the gut hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-2 (GLP-2; a representative of the intestinal proglucagon-derived peptides) after ingestion of glucose, fat, protein, and fructose, as well as their effects after parenteral administration in relation to bone turnover processes in healthy volunteers. Furthermore, we studied the effect on bone turnover of a single subcutaneous injection of GLP-2 in four different dosages (100, 200, 400, or 800 ,g GLP-2) or placebo in 60 postmenopausal women (mean age, 61 ± 5 years). Results: All macronutrients significantly (p < 0.05) reduced bone resorption as assessed by s-CTX (39,52% from baseline), and only the glucagon-like peptides were secreted in parallel. Parenteral administration of GIP and GLP-1 did not result in a reduction of the s-CTX level, whereas GLP-2 caused a statistically significant and dose-dependent reduction in the s-CTX level from baseline compared with placebo (p < 0.05). Urine DPD/creatinine, a marker of bone resorption, was significantly reduced by 25% from baseline in the 800-,g GLP-2 group (p < 0.01). An area under the curve (AUC0,8h) analysis for s-CTX after GLP-2 injection confirmed the dose-dependent decrease (ANOVA, p = 0.05). The s-osteocalcin level was unaffected by the GLP-2 treatment. Conclusion: These studies exclude both GIP and GLP-1 as key mediators for the immediate reduction in bone resorption seen after a meal. The dose-dependent reduction of bone resorption markers found after subcutaneous injection of GLP-2 warrants further investigation into the mechanism and importance of GLP-2 for the bone turnover processes. [source] Influence of CYP2C9 and CYP2C19 genetic polymorphisms on pharmacokinetics and pharmacodynamics of gliclazide in healthy Chinese Han volunteersJOURNAL OF CLINICAL PHARMACY & THERAPEUTICS, Issue 3 2010H. Shao PhD Summary Background and objective:,CYP2C9 is the major contributor to gliclazide metabolic clearance in vitro, while the pharmacokinetics of gliclazide modified release are affected mainly by CYP2C19 genetic polymorphisms in vivo. This study aims to investigate the influence of CYP2C9 and CYP2C19 genetic polymorphisms on the pharmacokinetics and pharmacodynamics of gliclazide in healthy Chinese Han volunteers. Methods:, Eighteen healthy Han subjects with various combinations of CYP2C9 and CYP2C19 genotypes received 80 mg gliclazide. Plasma gliclazide concentrations were measured by a liquid chromatography,tandem mass spectrometry method for 84 h and plasma glucose and insulin levels were measured up to 15 h post-dose. Results and discussion:, There was no difference in either pharmacokinetic and or pharmacodynamic parameters of gliclazide when group A (CYP2C9*1/*1, CYP2C19 extensive metabolizers) was compared with group B (CYP2C9*1/*3, CYP2C19 *1/*1). When group C (CYP2C9*1/*1 and CYP2C19 poor metabolizers) was compared with group A, the AUC0,, and Cmax in group C were significantly higher [83·94 ± 40·41 vs. 16·39 ± 5·10 ,g·h/mL (P = 0·000) and 1·50 ± 0·85 vs. 0·45 ± 0·18 ,g/mL (P = 0·000)], and the oral clearance was significantly lower [1·17 ± 0·63 vs. 5·38 ± 1·86 L/h (P = 0·000)]. The half-life of gliclazide was also significantly prolonged in group C subjects when compared with that of group A (33·47 ± 12·39 vs. 19·34 ± 10·45 h), but the difference was not significant (P = 0·052). The increase in serum glucose level at 11 h after dosing (,Cglu11) in group C was significantly higher than that of group A (,1·08 ± 0·42 vs. 0·22 ± 1·01 mmol/L, P = 0·022). The corresponding insulin levels showed no difference between the two groups. Conclusion:,CYP2C9*3 was not associated with any change in the disposition of gliclazide. CYP2C19 polymorphisms appear to exert the dominant influence on the pharmacokinetics of gliclazide in healthy Chinese Han subjects, and may also affect the observed pharmacodynamics of the drug as a result. [source] OATP1B1 388A>G polymorphism and pharmacokinetics of pitavastatin in Chinese healthy volunteersJOURNAL OF CLINICAL PHARMACY & THERAPEUTICS, Issue 1 2010J. Wen PhD Summary Purpose:, To investigate the contribution of the most frequent single nucleotide polymorphism (SNPs) of the organic anion transporting polypeptide 1B1 (OATP1B1) 388A>G to the pharmacokinetics of pitavastatin in Chinese healthy volunteers. Methods:, Eighteen healthy volunteers participated in this study. Group 1 consisted of nine subjects who were of 388AA wild-type OATP1B1 genotype. Group 2 consisted of seven subjects with the 388GA genotype and two 388GG homozygotes. Two milligram of pitavastatin was administered orally to the volunteers. The plasma concentration of pitavastatin was measured for up to 48 h by liquid chromatography,mass spectrometry (LC,MS). Results:, The pharmacokinetic parameters of pitavastatin were significantly different between the two genotyped groups. The concentration (Cmax) value was higher in the 388GA + 388GG group than that in the 388AA group (39·22 ± 8·45 vs. 22·90 ± 4·03 ng/mL, P = 0·006). The area under the curve to the last measurable concentration (AUC0,48) and area under the curve extrapolated to infinity (AUC0,,) of pitavastatin were lower in the 388AA group than in the 388GA + 388GG group (100·42 ± 21·19 vs. 182·19 ± 86·46 ng h/mL, P = 0·024; 108·12 ± 24·94 vs. 199·64 ± 98·70ng h/mL, P = 0·026) respectively. The oral clearance (Cl/F) was lower in the 388GA + 388GG group than that in the 388AA group (12·46 ± 4·79 vs. 19·21 ± 3·74/h, P = 0·012). The elimination of half-life (t1/2) and peak concentration times (Tmax) values showed no difference between these groups. Conclusions:, The OATP 388A>G polymorphism causes significant alterations in the pharmacokinetics of pitavastatin in healthy Chinese volunteers and this may well be clinically significant. [source] Pharmacokinetics and pharmacodynamics of prasugrel in subjects with moderate liver diseaseJOURNAL OF CLINICAL PHARMACY & THERAPEUTICS, Issue 5 2009D. S. Small PhD Summary Background and Objective:, Prasugrel is a thienopyridine antiplatelet agent under investigation for the prevention of atherothrombotic events in patients with acute coronary syndrome who undergo percutaneous coronary intervention. Patients with chronic liver disease are among those in the target population for prasugrel. As hepatic enzymes play a key role in formation of prasugrel's active metabolite, hepatic impairment could affect the safety and/or efficacy of prasugrel in such patients. Methods:, This was a parallel-design, open-label, multiple dose study of 30 subjects, 10 with moderate hepatic impairment (Child-Pugh Class B) and 20 with normal hepatic function. Prasugrel was administered orally as a 60-mg loading dose (LD) and daily 10-mg maintenance doses (MDs) for 5 days. Pharmacokinetic parameters (AUC0,t, Cmax and tmax) and maximal platelet aggregation (MPA) by light transmission aggregometry were assessed after the LD and final MD. Results and Discussion:, Exposure to prasugrel's active metabolite was comparable between healthy subjects and those with moderate hepatic impairment. Point estimates for the ratios of geometric least square means for AUC0,t and Cmax after the LD and last MD ranged from 0·91 to 1·14. MPA to 20 ,m ADP was similar between subjects with moderate hepatic impairment and healthy subjects for both the LD and MD. Prasugrel was well tolerated by all subjects, and adverse events were mild in severity. Conclusion:, Moderate hepatic impairment appears to have no effect on exposure to prasugrel's active metabolite. Furthermore, MPA results suggest that moderate hepatic impairment has little or no effect on platelet aggregation relative to healthy controls. Overall, these results suggest that a dose adjustment would not be required in moderately hepatically impaired patients taking prasugrel. [source] Smoking behaviour modulates pharmacokinetics of orally administered clopidogrelJOURNAL OF CLINICAL PHARMACY & THERAPEUTICS, Issue 4 2008A.-M. Yousef PhD Summary Background and objectives:, Clopidogrel is an important antiplatelet drug that is effective in preventing thrombotic events, especially for patients undergoing percutaneous coronary intervention. The therapeutic usefulness of clopidogrel has been limited by documented inter-individual heterogeneity in platelet inhibition, which may be attributable to known clopidogrel pharmacokinetic variability. The objective of this study was to assess the influence of smoking cigarettes and abnormal body weight on the pharmacokinetics of clopidogrel. Methods:, Seventy-six healthy adult male volunteers were selected randomly. Each subject received a single 75 mg oral dose of clopidogrel after overnight fast. Clopidogrel carboxylate plasma levels were measured and non-compartmental analysis was used to determine peak plasma concentration (Cmax), time to peak plasma concentration (Tmax), elimination half-life (t1/2e), and area under the curve (AUC0,,). Results:, One-third of volunteers were smokers (n = 27) and one-half had abnormal body weight (n = 39). Smokers had lower AUC0,, (smokers: 6·24 ± 2·32 ,g/h/mL vs. non-smokers: 8·93 ± 3·80 ,g/h/mL, P < 0·001) and shorter half-life (smokers: 5·46 ± 2·99 vs. non-smokers: 8·43 ± 4·26, P = 0·001). Smoking behaviour had no influence on Cmax (P = 0·3) and Tmax (P = 0·7). There was no statistically significant difference in Cmax, AUC0,,, Tmax and t1/2e between volunteers with abnormal body weight and normal body weight. However the difference in body weight of the two groups was relatively narrow (mean ± SE; 26·93 ± 0·16 vs. 23·11 ± 0·27). In general, the pharmacokinetic parameters were characterized by considerable inter-individual differences (Cmax = 3·09 ± 0·99 ,g/mL, CV = 32%), (Tmax =0·76 ± 0·24 h, CV = 31·6%), (AUC0,, = 7·98 ± 3·58 ,g/h/mL, CV = 44·8%), and (t1/2e = 7·38 ± 4·10 h, CV = 55·6%). Conclusion:, Smoking is a significant factor affecting the pharmacokinetics of clopidogrel, following administration of a single 75 mg dose in healthy young volunteers. The study supports smoking-cessation recommendations. Further studies are required to evaluate the influence of smoking and body weight on the pharmacokinetics of the active metabolite of clopidogrel and on the clinical effects of any differences observed. [source] Determination of glycyrrhetic acid in human plasma by HPLC-MS method and investigation of its pharmacokineticsJOURNAL OF CLINICAL PHARMACY & THERAPEUTICS, Issue 3 2008W.-J. Zhao PhD Summary Objective:, To develop a high performance liquid chromatography mass spectrometry (HPLC-MS) method for the determination of the glycyrrhetic acid (GA) in human plasma and for the investigation of its pharmacokinetics after the oral administration of 150 mg diammonium glycyrrhizinate test and reference capsule formulations. Methods:, The GA in plasma was extracted with ethyl acetate, separated on a C18 column with a mobile phase of methanol (5 mmol/L ammonium acetate),water (85 : 15, V/V) and analysed using a MS detector. Ursolic acid (UA) was used as internal standard. The target ions were m/z 469·5 for GA and m/z 455·6 for UA, the fragment voltages were 200 V and 100 V for GA and UA respectively. Results:, The calibration curve was linear over the range of 0·5,200 ng/mL (r = 0·9974). The limit of quantification for GA in plasma was 0·5 ng/mL, the recovery was 76·0,80·0%, and the inter- and intra-day relative standard deviations (RSD) were <12%. The pharmacokinetic parameters of GA after a single dose of 150 mg diammonium glycyrrhizinate test and reference were as follows: the half life (t1/2) 9·65 ± 3·54 h and 9·46 ± 2·85 h, the time to peak concentration (Tmax) 10·95 ± 1·32 h and 11·00 ± 1·30 h, the peak concentration (Cmax) 95·57 ± 43·06 ng/mL and 103·89 ± 49·24 ng/mL; the area under time-concentration curve (AUC0,48 and AUC0,,) 1281·84 ± 527·11 ng·h/mL and 1367·74 ± 563·27 ng·h/mL, 1314·32 ± 566·40 ng·h/mL and 1396·97 ± 630·06 ng·h/mL. The relative bioavailability of diammonium glycyrrhizinate capsule was 98·88 ± 12·98%. Conclusion:, The assay was sensitive, accurate and convenient, and can be used for the determination of GA in human plasma. Comparison of the bioavailability and pharmacokinetic profile of GA indicated that the test and reference capsules were bioequivalent. [source] Relationships of tacrolimus pharmacokinetic measures and adverse outcomes in stable adult liver transplant recipientsJOURNAL OF CLINICAL PHARMACY & THERAPEUTICS, Issue 1 2006C. Dansirikul PhD Summary Background and objectives:, Alternative measures to trough concentrations [non-trough concentrations and limited area under the concentration,time curve (AUC)] have been shown to better predict tacrolimus AUC. The aim of this study was to determine if these are also better predictors of adverse outcomes in long term liver transplant recipients. Methods:, The associations between tacrolimus trough concentrations (C0), non-trough concentrations (C1, C2, C4, C6/8), and AUC0,12 and the occurrence of hypertension, hyperkalaemia, hyperglycaemia and nephrotoxicity were assessed in 34 clinically stable liver transplant patients. Results and discussion:, The most common adverse outcome was hypertension, prevalence of 36%. Hyperkalaemia and hyperglycaemia had a prevalence of 21% and 13%, respectively. A sequential population pharmacokinetic/pharmacodynamic approach was implemented. No significant association between predicted C0, C1, C2, C4, C6/8 or AUC0,12 and adverse effects could be found. Tacrolimus concentrations and AUC measures were in the same range in patients with and without adverse effects. Conclusions:, Measures reported to provide benefit, preventing graft rejection and minimizing acute adverse effects in the early post-transplant period, were not able to predict adverse effects in stable adult liver recipients whose trough concentrations were maintained in the notional target range. [source] Reduced oral itraconazole bioavailability by antacid suspensionJOURNAL OF CLINICAL PHARMACY & THERAPEUTICS, Issue 3 2005M. Lohitnavy Summary Aims:, To investigate the effects of antacid suspension on oral absorption of itraconazole. Methods:, A randomized, open-labelled, two-period, crossover study with a 1-week washout period was conducted in 12 healthy Thai male volunteers. The participants were allocated in either treatment A or B in the first period. In treatment A, the volunteers were orally administered with 200 mg of itraconazole alone. In treatment B, the volunteers were administered orally with 200 mg of itraconazole co-administered with antacid suspension. Serial serum samples were collected over the period of 24 h and subsequently analysed by using a validated high-pressure liquid chromatographic method with ultraviolet detection. Pharmacokinetic parameters were determined by non-compartmental analysis. Results:, Time to reach maximal concentration (Tmax), maximal concentration (Cmax) and area under the curve (AUC0--,) were markedly decreased in antacid-treated group. Tmax for treatment A was 3·0 ± 0·4 and 5·1 ± 2·7 h for treatment B. Cmax and AUC0--, of treatments A and B were 146·3 ± 70·5 vs. 43·6 ± 16·9 (ng/mL) and 1928·5 ± 1114·6 vs. 654·8 ± 452·2 (ng·h/mL) respectively. 90% Confidence interval (90% CI) of Cmax and AUC0--, were 24·1,42·1 and 16·2,65·9 respectively. Conclusions:, Rate and extent of itraconazole oral absorption were markedly decreased by concurrent use of antacid suspension. Hence, co-administration of itraconazole and antacid suspension should be avoided. [source] Ketoconazole increases plasma concentrations of antimalarial mefloquine in healthy human volunteersJOURNAL OF CLINICAL PHARMACY & THERAPEUTICS, Issue 3 2005W. Ridtitid MD FCFPT Summary Background:, Antimalarial mefloquine has a structure related to quinine. The major metabolite of quinine is 3-hydroxyquinine formed by cytochrome P450 3A4 (CYP3A4). Ketoconazole, a potent inhibitor of CYP3A4, is known to markedly increase plasma concentrations of various co-administered drugs including quinine. Objective:, To assess the effect of ketoconazole on plasma concentrations of mefloquine in healthy Thai male volunteers. Methods:, In an open, randomized two-phase crossover study separated by a 1-month period, eight healthy Thai male volunteers received a single oral dose of 500 mg mefloquine alone or co-administration with 400 mg/day ketoconazole orally for 10 days. Serial blood samples were collected at specific time points for a 56-day period. Plasma mefloquine and mefloquine carboxylic metabolite concentrations during 56 days were measured by a modified and validated high-performance liquid chromatographic method with UV detection. Results:, Co-administration with ketoconazole markedly increased the mean values of mefloquine AUC0,t, t1/2, and Cmax when compared with mefloquine alone by 79% (P < 0·001), 39% (P < 0·05) and 64% (P < 0·001) respectively. The AUC0,t,, and Cmax of mefloquine carboxylic acid metabolite were decreased by 28% (P < 0·05) and 31% (P < 0·05), respectively when compared with mefloquine alone. Conclusions:, Co-administration with ketoconazole increased plasma mefloquine concentrations in healthy human volunteers. One of possible mechanisms of the increase in plasma mefloquine concentrations may be the result of the inhibition of CYP3A4 by ketoconazole. In case of mefloquine is co-administered with ketoconazole, drug,drug interactions should be recognized and the dose of mefloquine should be adjusted to maximize the therapeutic efficacy and to reduce the cost of therapy. [source] Pharmacokinetics of liquiritigenin in mice, rats, rabbits, and dogs, and animal scale-upJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 11 2009Hee E. Kang Abstract Pharmacokinetics of liquiritigenin (LQ) and its two glucuronide metabolites, M1 and M2, in mice, rats, rabbits, and dogs and animal scale-up of the pharmacokinetic parameters of LQ were evaluated. After intravenous administration of LQ, the AUC (AUC0,t) values of LQ, M1, and M2 were proportional to LQ doses in all animals studied. Animal scale-up of some pharmacokinetic parameters of LQ was performed based on the parameters after its intravenous administration (20 mg/kg; in the linear pharmacokinetic range) to the four species. Linear relationships were obtained (r,>,0.968) between log CL (or CL/fu) (L/h) and log species body weight (W) (kg) [CL (or CL/fu),=,3.29 (34.0) W0.723 (0.789)] and log,Vss (or Vss/fu) (L) and log,W (kg) [Vss (or Vss/fu),=,0.340 (3.52) W0.882 (0.948)]. Interspecies scale-up of plasma concentration,time data of LQ using apolysichron (complex Dedrick plots) resulted in similar profiles, and plasma concentration,time profile of humans were predicted using the well-fitted four animal data. Our results indicate that the LQ data obtained from laboratory animals could be utilized to generate preliminary estimates of the pharmacokinetic parameters of LQ in humans. These parameters can serve as guidelines for better planning of clinical studies. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:4327,4342, 2009 [source] Single-dose study to compare the pharmacokinetics of HFA flunisolide and CFC flunisolideJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 2 2002Arno Nolting Abstract The hydrofluoroalkane (HFA) formulation of the inhaled corticosteroid flunisolide is a modification of the original chlorofluorocarbon (CFC) formulation. HFA flunisolide replaces CFC with an HFA propellant and uses a built-in spacer in its pressurized metered-dose inhaler. The average HFA flunisolide particle size is 1.2 ,m compared with 3.8 ,m for the CFC formulation. The smaller particle size improves lung targeting, allowing a reduction in the HFA flunisolide dose relative to CFC flunisolide while maintaining comparable efficacy. In a study of 12 healthy men, pharmacokinetic parameters were determined after single doses of 1000 ,g CFC flunisolide delivered without a spacer, 340 ,g HFA flunisolide delivered through a spacer, and 516 ,g HFA flunisolide delivered without a spacer. A standard noncompartmental analysis of the concentration data was performed and mean (±,S.D.) pharmacokinetic values were reported. Peak plasma concentrations (observed Cmax) were similar for the three treatments. Area under the curve up to the time corresponding to the last measurable concentration (AUC0,tlast) was similar for the CFC and HFA flunisolide, plus spacer groups (4.4,±,1.6 ng·h/mL and 5.0,±,4.2 ng·h/mL, respectively); however, AUC0,tlast for the HFA flunisolide without spacer group was comparatively lower than for the CFC group (3.5,±,1.6 ng·h/mL). Observed Cmax and AUC0,tlast for 6,-OH flunisolide, the first-pass metabolite of flunisolide and an indicator of oropharyngeal deposition, were significantly higher in the CFC flunisolide group than in either HFA flunisolide group. © 2002 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 91:424,432, 2002 [source] Effect of lansoprazole and rabeprazole on tacrolimus pharmacokinetics in healthy volunteers with CYP2C19 mutationsJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 8 2004Fumio Itagaki The aim of this study was to investigate the effects of the proton pump inhibitors (PPIs), lansoprazole and rabeprazole, on tacrolimus pharmacokinetics in healthy volunteers with mutations in the cytochrome P450 (CYP) 2C19 gene (CYP2C19). An open-label crossover study was performed with 19 healthy subjects. Tacrolimus (2 mg) was administered orally with and without lansoprazole (30 mg per day for 4 days) or rabeprazole (10 mg per day for 4 days). Blood concentrations of tacrolimus were determined before and 1, 2, 4 and 8 h after dosing. Genotyping for CYP2C19 was conducted by a polymerase chain reaction-restriction fragment length polymorphism method. Coadministration of lansoprazole significantly decreased the oral tacrolimus clearance, resulting in an increase in the area under the blood concentration-time curve (AUC0,8) (control vs with lansoprazole: 29.7 ± 3.5 vs 44.1 ± 5.0 ng h mL,1, P<0.05). Large individual variation was observed in the effects of lansorazole on tacrolimus AUC0,8 owing to CYP2C19 genotype status. The percent change for tacrolimus AUC0,8 in subjects with and without CYP2C19 mutant alleles was 81% and 29%, respectively. Coadministration of rabeprazole also increased the mean AUC0,8 of tacrolimus, but the difference was not statistically significant. These observations suggest that drug interaction between tacrolimus and lansoprazole occurs in subjects with higher lansoprazole blood concentrations corresponding to CYP2C19 genetic status. In contrast, rabeprazole has minimal effect on tacrolimus pharmacokinetics regardless of CYP2C19 genotype status. [source] The Effect of Different Dosing Schedules of UCN-01 on its Pharmacokinetics and Cardiohaemodynamics in DogsJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 11 2000N. KURATA 7-Hydroxy-staurosporine (UCN-01) is now under development as a novel anticancer drug. In clinical studies, different infusion schedules are being investigated in the USA and Japan. To examine the effect of different infusion schedules on the pharmacokinetics and cardiohaemodynamics of UCN-01, dogs were treated with UCN-01 as either a 3-h or a 24-h constant intravenous infusion. Blood pressure and heart rate, together with UCN-01 concentrations during and after infusion, were monitored. To analyse the relationship between the pharmacokinetics and cardiohaemodynamics of UCN-01, the plasma concentration of UCN-01 at the end of infusion (Cend), the area under the plasma concentration versus time curves (AUC0-,) and the mean residence time (MRT) were used. As indices of cardiohaemodynamic changes, the area under decreasing systolic blood pressure and increasing heart rate versus time curves (dAUCpressure and AUCheart rate) were calculated by the trapezoidal method. For the 3-h (0.22 and 0.65 mgkg,1) and 24-h infusion (0.81 to 6.48 mgkg,1), systolic and diastolic blood pressures fell after or during infusions, accompanied by a dose-dependent increase in heart rate for both infusions. During both infusion schedules, the plasma concentrations of UCN-01 gradually increased and Cend showed a dose-proportional increase. After that, UCN-01 was eliminated bi-exponentially with an elimination half-life of 5.14 ± 1.12 to 8.32 ± 1.80 h. The total clearance (CLtotal) ranged from 0.383 to 0.666 ± 0.149L h,1kg,1. There was no significant difference in these parameters among the doses in each infusion schedule, indicating that UCN-01 has a linear pharmacokinetic profile over the dose range examined for each infusion, and there were also no significant differences between the 3-h and 24-h infusion except for MRT. The pharmacokinetic parameters of Cend, AUC0-, and slope0-3h exhibited a degree of correlation with the AUCheart rate in the 3-h infusion and correlated significantly with the dAUCpressure in the 24-h infusion. The MRT did not correlate with cardiohaemodynamic changes during either infusion. In conclusion, the pharmacokinetic profile of UCN-01 after the shorter infusion is similar to that after the longer one. However, a longer dosing period of UCN-01 increased the residence time in comparison with the shorter infusion. This may be due to the effect on the circulatory function in dogs. [source] Controlled Transdermal Delivery of Propranolol Using HPMC Matrices: Design and In-vitro and In-vivo EvaluationJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 2 2000P. R. P. VERMA To improve bioavailability and achieve a smoother plasma-concentration profile as compared with oral administration, a matrix-dispersion-type transdermal delivery system was designed and developed for propranolol using different ratios of hydroxypropyl-methylcellulose (HPMC) K4M, K15M and K100M. Formulations were evaluated for in-vitro dissolution characteristics using a Cygnus' sandwich-patch holder. Drug release followed Higuchi rather than zero-order or first-order kinetics. In-vivo evaluation was carried out on healthy volunteers (21 ± 1.41 years; 60.89 ± 5.35 kg) following the balanced incomplete block design. The dissolution rate constant (k) and data generated from plasma and urine (Cmax, maximum plasma concentration; tmax, time to reach peak plasma concentration; AUC, area under the curve; ke, elimination rate constant; t½e, elimination half-life; ka, absorption rate constant; t½a, absorption half-life) were evaluated statistically by two-way analysis of variance. Statistically excellent correlation was found between the percentage of drug absorbed and Cmax, AUC0,24 and AUC0-,. A highly significant difference (P < 0.001) was observed when Cmax and AUC0-, generated from plasma and urine were compared, but ke, t½e, ka and t½a did not differ significantly (P > 0.1). We conclude that urinary excretion data may be used as a simpler alternative to blood level data in studying the kinetics of absorption and deriving the absorption parameters. [source] Evaluation of the Effect of Ethanol's Toxic Metabolite Acetaldehyde on the Gastrointestinal Oligopeptide Transporter, PEPT1: In Vitro and in Vivo StudiesALCOHOLISM, Issue 1 2008Scott J. Fisher Background:, The effects of alcohol consumption and its subsequent metabolism on drug transport, absorption and pharmacokinetics are poorly understood. This study examines the effects of the ethanol metabolite, acetaldehyde, on the clinically relevant drug transporter, PEPT1. The metabolism of ethanol and the following acetaldehyde formation is thought to modulate the uptake capacity of PEPT1 within the gastrointestinal tract for a variety of clinically important peptidomimetic drug compounds. Methods:, Glycylsarcosine ([3H]-GlySar), a nonhydrolysable PEPT1 specific substrate was used in our studies. In vitro uptake studies were performed in the Caco-2 and Chinese hamster ovary (CHO)-hPEPT1 cell models, measuring cellular uptake of labeled compound against increasing levels of unlabeled compound in the presence of acetaldehyde. In vivo absorption of [3H]-GlySar was measured in male Sprague,Dawley rats that were treated with oral dose of ethanol/disulfiram (5 g/kg / 100 mg/kg) for 6 days. These results were compared to control rats treated with saline, ethanol alone or disulfiram alone. Results:, In vitro uptake of [3H]-GlySar in CHO-hPEPT1 cells treated with 1 mM acetaldehyde was significantly decreased (p < 0.05) as compared to untreated controls. The uptake of [3H]-GlySar in Caco-2 cell monolayers treated with 1 mM acetaldehyde was also significantly decreased as compared to the untreated control cells. In vivo absorption of [3H]-GlySar in ethanol treated rats, as measured by AUC0,12 hours were decreased by approximately 50% versus the control rat group. Conclusion:, The effects of acetaldehyde due to consumption of ethanol on the uptake and bioavailability of therapeutic drug compounds transported by the PEPT1 oligopeptide transporter have not been documented. In the present studies, we demonstrate that acetaldehyde significantly modulates PEPT1 function and, thereby, affects drug bioavailability. To our best knowledge, this is the first report on the effects of an ethanol metabolite on substrate absorption in the gastrointestinal tract, rather than interactions in the liver, which is an under-represented area of research in alcohol pathophysiology. [source] Automated determination of venlafaxine in human plasma by on-line SPE-LC-MS/MS.JOURNAL OF SEPARATION SCIENCE, JSS, Issue 4 2009Application to a bioequivalence study Abstract A new automated SPE-LC-ESI-MS/MS method was developed and validated to quantify venlafaxine in human plasma using fluoxetine as an internal standard. The analytes were automatically extracted from plasma by C18 SPE cartridges, separated on a C8 RP column and analyzed by MS in the multiple reaction-monitoring (MRM) mode. The method has a chromatographic run time of 4.0 min and a linear calibration curve over the range of 0.25,200 ng/mL (r >0.997). The between-run precisions, based on the percent RSD for replicate quality controls (0.75; 80, and 200 ng/mL), were < 8.5% for all concentrations. The between-run accuracies, based on the percent relative error, were < 4.0%. This method was successfully employed in a bioequivalence study of two venlafaxine capsule formulations (test formulation from Eurofarma (Brazil) and Efexor XR, reference formulation, from Wyeth-Whitehall, Brazil) in 48 healthy volunteers of both sexes who received a single 150 mg dose of each formulation. More than 3000 samples were analyzed eliminating the analyst's exposure to hazardous organic solvents normally employed in off-line liquid,liquid extractions. The 90% confidence interval (CI) of the individual ratio geometric mean for Test/Reference was 91.6,103.4% for AUC0,48 h and 102.2,112.6% for Cmax. Since both 90% CI for AUC0,48 h and Cmax were included in the 80,125% interval proposed by the US Food and Drug Administration (FDA) and the Brazilian National Health Surveillance Agency (ANVISA), the test formulation was considered bioequivalent to Efexor XR according to both the rate and extent of absorption. [source] Impact of ribavirin plasma level on sustained virological response in patients treated with pegylated interferon and ribavirin for chronic hepatitis CALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 5 2009D. BREILH Summary Background, The main goal of therapy in hepatitis C virus (HCV) infection is to achieve a sustained virological response (SVR). However, the impact of the pharmacological properties of ribavirin on the SVR has not been fully investigated. Aim, To evaluate, through a prospective study, the association between ribavirin plasma level and SVR response in HCV patients treated with pegylated interferon (PEG-IFN) and ribavirin. Patients and methods, Patients treated with PEG-IFN and ribavirin had plasmatic ribavirin dosage at weeks 4 and 12. SVR was evaluated 6 months after the end of treatment. Results, At week 4, a strong correlation was found between HCV-RNA and Cmin of ribavirin plasma level (r = ,0.376, P = 0.002) and AUC0,12h of ribavirin plasma level (r = ,0.277, P = 0.018). At week 12, a strong correlation was found between HCV-RNA and Cmin of ribavirin plasma level (r = ,0.384, P < 0.0001) and AUC0,12h of ribavirin plasma level (r = ,0.257, P = 0.002). In genotype 1 patients, AUC0,12h ribavirin and Cmin were significantly correlated with negative HCV-RNA at week 12 and SVR. In the multiple logistic regression model, the only factor independently associated with SVR in genotype 1 patients was negative HCV-RNA at week 12. Conclusion, Cmin of ribavirin at weeks 4 and 12 was significantly higher in sustained virological responders compared with relapser or nonresponder patients. However, in genotype 1 patients, plasma ribavirin level at weeks 4 and 2 was not associated with SVR. [source] The disposition of free and niosomally encapsulated Rac-flurbiprofen in dairy bovinesJOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 1 2010E. O. CONFALONIERI Confalonieri, E. O., Soraci, A. L., Becaluba, M., Denzoin, L., Rodriguez, E., Riccio, B., Tapia, O. The disposition of free and niosomally encapsulated Rac-flurbiprofen in dairy bovines. J. vet. Pharmacol. Therap. 33, 9,14. Pharmacokinetic parameters were established for flurbiprofen (FBP) after intravenous (i.v.) administration (0.5 mg/kg) of niosomal and nonniosomal formulations in dairy cattle. Niosomes of FBP showed a drug loading of 92.0 ± 0.7% and the intravenous administration of the FBP niosomes to dairy cattle did not produce any immunological reaction associated to niosomal components. Niosomal FBP was slowly eliminated from plasma and mean residual time (MRT) and AUC0,t and t 1/2 values were significantly higher than those for non niosomal FBP formulations. The results presented in this study indicate that the long circulation of FBP niosomes offers a potential application for improving the pharmacokinetic parameters of short half-life drugs for clinical use. Niosomes offer new promising perspectives of drug delivery modules in bovine therapeutics. [source] Kinetics and residues after intraperitoneal procaine penicillin G administration in lactating dairy cowsJOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 3 2009A. L. CHICOINE This paper describes the pharmacokinetic profile of procaine penicillin G after intraperitoneal (IP) administration in eight lactating dairy cows. Procaine pencillin G (PPG, 21 000 IU/kg) was deposited into the abdominal cavity of each cow following an incision in the right paralumbar fossa. Blood and milk samples were taken over the following 10 days, at which point the cows were euthanized. Plasma, milk, muscle, liver, and kidney penicillin concentrations were determined by HPLC, with a limit of quantification of 5 ng/mL for plasma and milk and 40 ng/g for tissue samples. A noncompartmental method was used to analyze plasma kinetics. The mean pharmacokinetic parameters (±SD) were: Cmax, 5.5 ± 2.6 ,g/mL; Tmax, 0.75 ± 0.27 h; AUC0-,, 10.8 ± 4.9 ,g·h/mL; MRT, 2.2 ± 0.9 h. All milk from treated cows contained detectable penicillin residues for a minimum of three milkings (31 h) and maximum of five milkings (52 h) after administration. Concentrations of penicillin in all muscle, liver, and kidney samples taken 10 days postadministration were below the limit of quantification. Necropsy examinations revealed foci of hemorrhage on the rumenal omentum of most cows but peritonitis was not observed. Systemic inflammation as determined by change in leukogram or plasma fibrinogen was noted in one cow. The results of this study demonstrate that IP PPG is absorbed and eliminated rapidly in lactating dairy cows. [source] Pharmacokinetics of erythromycin in nonlactating and lactating goats after intravenous and intramuscular administrationJOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 1 2007L. AMBROS The objectives of this work were to compare the pharmacokinetics of erythromycin administered by the intramuscular (i.m.) and intravenous (i.v.) routes between nonlactating and lactating goats and to determine the passage of the drug from blood into milk. Six nonpregnant, nonlactating and six lactating goats received erythromycin by the i.m. (15 mg/kg) and the i.v. (10 mg/kg) routes of administration. Milk and blood samples were collected at predetermined times. Erythromycin concentrations were determined by microbiological assay. Results are reported as mean ± SD. Comparison of the pharmacokinetic profiles between nonlactating and lactating animals after i.v. administration indicated that significant differences were found in the mean body clearance (8.38 ± 1.45 vs. 3.77 ± 0.83 mL/kg·h respectively), mean residence time (0.96 ± 0.20 vs. 3.18 ± 1.32 h respectively), area under curve from 0 to 12 h (AUC0,12) (1.22 ± 0.22 vs. 2.76 ± 0.58 ,g·h/mL respectively) and elimination half-life (1.41 ± 1.20 vs. 3.32 ± 1.34 h); however, only AUC0,12 showed significant differences after the i.m. administration. Passage of erythromycin in milk was high (peak milk concentration/peak serum concentration, 2.06 ± 0.36 and AUC0,12milk/AUC0,12serum,6.9 ± 1.05 and 2.37 ± 0.61 after i.v. and i.m. administrations respectively). We, therefore, conclude that lactation affects erythromycin pharmacokinetics in goats. [source] Comparative serum pharmacokinetics of the fluoroquinolones enrofloxacin, difloxacin, marbofloxacin, and orbifloxacin in dogs after single oral administrationJOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 1 2002E. HEINEN The pharmacokinetics after oral application of the fluoroquinolones (FQs), enrofloxacin, difloxacin, marbofloxacin and orbifloxacin were compared in independent crossover studies in Beagle dogs. Commercially available tablet formulations were given at common dosage recommended by the manufacturers which were 2.0 mg/kg body weight (bw) for marbofloxacin, 2.5 mg/kg bw for orbifloxacin and 5.0 mg/kg bw for enrofloxacin and difloxacin. Analysis was performed by an agar diffusion assay. Pharmacokinetic parameters were calculated by noncompartmental methods. All FQs were rapidly absorbed and achieved average peak serum concentrations of 1.41, 1.11, 1.47 and 1.37 ,g/mL for enrofloxacin, difloxacin, marbofloxacin and orbifloxacin, respectively. Enrofloxacin was eliminated at a terminal half-life (t½) of 4.1 h, difloxacin at 6.9 h, orbifloxacin at 7.1 h and marbofloxacin at 9.1 h. While the area under the serum concentration,time curve of the 24-h dosing interval (AUC0,24) for marbofloxacin and orbifloxacin were similar (approximately 13 ,g · h/mL), enrofloxacin attained an AUC0,24 of 8.7 and difloxacin of 9.3 ,g · h/mL. Because of its favourable pharmacokinetics combined with excellent in vitro activity, enrofloxacin exhibited superior pharmacodynamic predictors of in vivo antimicrobial activity as Cmax/MIC (maximum serum concentration/minimum inhibitory concentration) and AUC0,24/MIC (area under the 24-h serum concentration,time curve/minimum inhibitory concentration) compared with other FQs. [source] Cyclosporine exposure and calcineurin phosphatase activity in living-donor liver transplant patients: Twice daily vs. once daily dosingLIVER TRANSPLANTATION, Issue 2 2006Masahide Fukudo We have compared the pharmacokinetics and pharmacodynamics of cyclosporine between once- and twice-daily dosing regimens in de novo patients of living-donor liver transplantation (LDLT). A total of 14 patients were enrolled in this study, who had received cyclosporine microemulsion (Neoral) twice a day (BID, n = 5) or once daily in the morning (QD, n = 9) after transplantation. On postoperative day (POD) 6, the QD regimen significantly increased cyclosporine exposure; the blood concentration at 2 hours postdose (C2) and area under the concentration-time curve (AUC) for 4 hours (AUC0,4), compared with the BID regimen. Moreover, the area under the calcineurin (CaN) activity in peripheral blood mononuclear cells time-curve (AUA) for 12 hours (AUA0,12) and 24 hours (AUA0,24) were decreased by approximately 42 and 25% with the QD regimen relative to the BID regimen, respectively. The C2 level was significantly correlated with the AUC0,4 (r2 = 0.95), which was negatively related to the AUA0,12 with a large interindividual variability (r2 = 0.59). However, a significant correlation was found between the AUA0,12 or AUA0,24 and CaN activity at trough time points. According to a maximum inhibitory effect attributable to the drug (Emax) model, the mean estimates of Emax and the Cb value that gives a half-maximal effect (EC50) for CaN inhibition were not significantly different between the 2 groups, respectively. These findings suggest that a once daily morning administration of cyclosporine may improve oral absorption and help to provide an effective CaN inhibition early after LDLT. Furthermore, CaN activity at trough time points would be a single surrogate predictor for the overall CaN activity throughout dosing intervals following cyclosporine administration. Liver Transpl 12:292,300, 2006. © 2006 AASLD. [source] Characterization of sirolimus metabolites in pediatric solid organ transplant recipientsPEDIATRIC TRANSPLANTATION, Issue 1 2009Guido Filler Abstract:, Potential age-dependent changes of sirolimus metabolite patterns in pediatric renal transplant recipients remain elusive. Thirteen pediatric solid organ transplant recipients (10 kidney, one combined liver,kidney, two liver, mean age 8.0 ± 5.0 yr) underwent a sirolimus pharmacokinetic profile in steady-state with 10 samples drawn over 12 h post-intake to calculate the AUC0,12 h. Concentrations of sirolimus and metabolite were quantified using a validated LC-MS/MS assay and metabolite structures were identified directly in blood extracts using LC-MS/iontrap. Average sirolimus AUC0,12 h was 64.9 ± 29.7 ng h/mL. Median (range) AUC0,12 h for each metabolite (ng h/mL) was: 12-hydroxy-sirolimus 7.6 (0.2,18.8), 46-hydroxy sirolimus 3.1 (0.0,12.4), 24-hydroxy sirolimus 4.3 (0.0,12.6), piperidine-hydroxy sirolimus 3.5 (0.0,8.3), 39- O -desmethyl sirolimus 3.6 (0.0,11.3), 16- O -desmethyl sirolimus 5.0 (0.1,9.9), and di-hydroxy sirolimus 4.3 (0.0,32.5). The metabolites reached a median total AUC0,12 h of 60% of that of sirolimus. The range was 2.6,136%, indicating significant variability. In all, 77.5% of the metabolites were hydroxylated, while 39- O -desmethyl sirolimus accounted for only 8.4% of the AUC0,12 h. This is clinically relevant as 39- O -desmethyl sirolimus shows 86,127% cross-reactivity with the antibody of the widely used Abbott sirolimus immunoassay. The metabolism of sirolimus in the children included in our study differed from that reported in adults, which should be considered when monitoring sirolimus exposure immunologically. [source] | ||||||||||||||||||||||||||||