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Peak Plasma Concentration (peak + plasma_concentration)
Selected AbstractsAtomised lidocaine for airway topical anaesthesia in the morbidly obese: 1% compared with 2%,ANAESTHESIA, Issue 1 2010C. Woodruff Summary Airway anaesthesia using atomised lidocaine for awake oral fibreoptic intubation in morbidly obese patients was evaluated using two doses of local anaesthetic. In this randomised, blinded prospective study, 40 ml of atomised 1% (n = 11) or 2% (n = 10) lidocaine was administered with high oxygen flow as carrier. Outcomes included time for intubation, patient tolerance to airway manipulation, haemodynamic parameters, the bronchoscopist's overall satisfaction, and serial serum lidocaine concentrations. Patients receiving lidocaine 1% had a longer mean (SD) time from the start of topicalisation to tracheal tube cuff inflation than those receiving lidocaine 2% (8.6 (0.9) min vs 6.9 (0.5) min, respectively; p < 0.05). Patients in the 1% cohort demonstrated increased responses to airway manipulation (p < 0.0001), reflecting lower bronchoscopist's satisfaction scores (p < 0.03). Haemodynamic responses to topicalisation and airway manipulation were similar in both groups. Peak plasma concentration was lower in the 1% group (mean (SD) 1.4 (0.3) and 3.8 (0.5) ,g.ml,1, respectively; p < 0.001). Airway anaesthesia using atomised lidocaine for awake oral fibreoptic intubation in the morbidly obese is efficacious, rapid and safe. Compared with lidocaine 1%, the 2% dose provides superior intubating conditions. [source] Comparative pharmacokinetics of single doses of doxylamine succinate following intranasal, oral and intravenous administration in ratsBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 6 2002Andries Pelser Abstract The intranasal route of administration provides a potential useful way of administering a range of systemic drugs. In order to assess the feasibility of this approach for the treatment of nausea and vomiting, doxylamine succinate was studied in rats for the pharmacokinetics (AUC, Cmax, tmax) following intranasal, oral and intravenous administrations. Subjects (six male Sprague,Dawley rats per time interval for each route of administration) received 2-mg doses of doxylamine succinate orally and I-mg doses intranasally and intravenously, respectively. The various formulations were formulated in isotonic saline (0.9% w/v) at 25±1°C. Doxylamine succinate concentrations in plasma were determined with a high-performance liquid chromatographic assay and a liquid,liquid extraction procedure. Intranasal and oral bioavailabilities were determined from AUC values relative to those after intravenous dosing. Intranasal bioavailability was greater than that of oral doxylamine succinate (70.8 vs 24.7%). The intranasal and oral routes of administration differed significantly from the intravenous route of administration. Peak plasma concentration (Cmax) was 887.6 ng/ml (S.D. 74.4), 281.4 ng/ml (S.D. 24.6) and 1296.4 ng/ml (S.D. 388.9) for the intranasal, oral and intravenous routes, respectively. The time to achieve Cmax for the intranasal route (tmax=0.5 h) was faster than for the oral route (tmax=1.5 h), but no statistically significant differences between the Cmax values were found using 95% confidence intervals. The results of this study show that doxylamine succinate is rapidly and effectively absorbed from the nasal mucosa. Copyright © 2002 John Wiley & Sons, Ltd. [source] Femoral nerve block with ropivacaine or bupivacaine in day case anterior crucial ligament reconstructionACTA ANAESTHESIOLOGICA SCANDINAVICA, Issue 4 2010H. WULF Background/Objective: Our aim was to evaluate analgesia, motor block and pharmacokinetics of ropivacaine 0.2% and 0.75% in a femoral nerve block (FNB) in day case patients for anterior crucial ligament (ACL)-reconstruction compared with bupivacaine 0.25% and placebo. Methods: Following ethics committee approval and informed consent, 280 patients were randomly allocated to four groups for single-shot FNB [30 ml ropivacaine 0.2% (group RO2.0), 0.75% (RO7.5), bupivacaine 0.25% (BU2.5) and NaCl 0.9% (NaCl)]. Analgesia (pain scores, primary outcome) and motor block were assessed at 4 h (dismissal) and up to 24 h. Plasma concentration was determined up to 240 min thereafter. Results: Pain scores at 4 h were significantly higher for NaCl 4 (0,8) (median, range) (vs.) BU2.5 2 (0,8), RO2.0 3 (0,9) and RO7.5 2 (0,8) (NS within the LA groups). Patients of the NaCl group needed analgesics significantly more often (93%) within 4 h after surgery vs. 16% of group RO2.0, 19% of group RO7.5 and 19% of group BU2.5. Motor block was significantly increased with all local anesthetics without a significant difference within the LA groups 3 (0,5) in RO2.0, 3 (0,5) in RO7.5 and 3 (0,4) in BU2.5 vs. 0 (0,3) in group NaCl (median (range); scale from 0=full strength to 5=complete paralysis). Peak plasma concentrations differed significantly: RO7.5: 1.4 ± 0.4 (0.73,2.6) [,g/ml, mean ± SD (range)] after 33 ± 14 (10,40) min, RO2.0: 0.6 ± 0.3 (0.13,1.0) after 22+17 (10,60) and BU2.5: 0.3 ± 0.16 (0.05,0.62) at 31 ± 17 (10,60), respectively. Conclusion: FNB for ACL reconstruction with ropivacaine or bupivacaine provided better post-operative analgesia than placebo without reaching toxic plasma concentrations. Significant motor block was observed after 4 h in all groups including the lowest concentration of ropivacaine but occurred even with placebo. [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] Single and multiple-dose pharmacokinetics of tepoxalin and its active metabolite after oral administration to rabbits (Oryctolagus cuniculus)JOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 2 2008C. G. POLLOCK The anti-inflammatory agent, tepoxalin, was administered to eight healthy 6-month-old female New Zealand white rabbits once daily at an oral dose of 10 mg/kg. Blood samples were obtained immediately before and at 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 h postadministration on days 1 and 10. Tepoxalin and its active metabolite, RWJ 20142, concentrations were determined in plasma by use of high-performance liquid chromatography with mass spectrometry. Cmax of the parent compound was reached between 3 and 8 h of drug administration, with a harmonic mean t1/2 of 3.6 h. Peak tepoxalin plasma concentrations were 207 ± 49 ng/mL. After oral administration, the metabolite RWJ 20142 achieved Cmax in plasma 2,8 h after administration, with a t1/2 of 1.9,4.8 h (harmonic mean 2.8 h). Peak plasma concentrations of RWJ 20142 on day 1 were 2551 ± 1034 ng/mL. [source] Comparison of the pharmacokinetics of moxidectin and ivermectin after oral administration to beagle dogsBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 8 2007Sayer I. Al-Azzam Abstract This study compares plasma disposition kinetics of ivermectin and moxidectin after oral administration to beagle dogs experimentally infected with the filarial parasite, Brugia pahangi. Sixteen dogs were selected and randomly allocated into two groups of eight dogs each. Animals in each group received either ivermectin or moxidectin by oral route at a dose of 250 µg/kg. Blood samples were collected from 0.5 h up to 56 days post-treatment and the plasma was analysed by high performance liquid chromatography (HPLC). The obtained data were analysed by compartmental and non-compartmental pharmacokinetic techniques. Peak plasma concentrations (Cmax) of 234.0 ± 64.3 ng/ml (mean ± SD) were obtained for moxidectin and 132.6 ± 43.0 ng/ml for ivermectin. The terminal elimination half-life was significantly (p<0.01) longer in the moxidectin treated group (621.3 ± 149.3 h) than for ivermectin treated group (80.3 ± 29.8 h). A significantly (p< 0.01) larger Vss/F was obtained for moxidectin (19.21 ± 3.61 l/kg) compared with ivermectin (5.35 ± 1.29 l/kg). The mean estimates of CL/F of moxidectin and ivermectin were 0.0220 ± 0.00381 and 0.0498 ± 0.0179 l/h/kg, respectively. The comparative plasma disposition kinetics of ivermectin and moxidectin in dogs is reported for the first time. Copyright © 2007 John Wiley & Sons, Ltd. [source] Pharmacokinetics and safety of oral almotriptan in healthy male volunteersBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 7 2004J. McEwen Abstract Almotriptan (LAS 31416) is a new, oral, specific 5-hydroxytryptamine1B/1D receptor agonist for the treatment of migraine. The pharmacokinetics and safety of a range of oral doses were assessed in 23 healthy male volunteers. Peak plasma concentrations were reached between 1.5 and 4 h after dosing. The maximum plasma concentration and area under the curve showed dose proportionality over the dose range 5,200 mg. The elimination half-life was constant at approximately 3 h across all dose levels. A substantial proportion of the initial dose was excreted in urine (27%,39%) during 12 h post-dose and the main excretory product was unchanged drug. Three major urinary metabolites were detected, all of which were pharmacologically inactive. The most common events following almotriptan administration were headache, tiredness and mild nausea. Nine events (18%) were classed as probably related to almotriptan and these were all at the highest dose level of 200 mg. The maximum tolerated dose of almotriptan was, therefore, determined as 150 mg. In conclusion, almotriptan is well tolerated following single, oral doses up to 150 mg and has predictable pharmacokinetics. Copyright © 2004 John Wiley & Sons, Ltd. [source] Simultaneous fitting of R- and S-ibuprofen plasma concentrations after oral administration of the racemateBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 4 2001Jörn Lötsch Aims, To assess the pharmacokinetic equivalence of two different formulations of ibuprofen lysinate with special focus on the expected effects. Methods, Sixteen healthy volunteers received cross-over ibuprofen lysinate as either one tablet of 400 mg (,test') or two tablets of 200 mg (,reference'). Ibuprofen plasma concentrations were followed up for 10 h. Bioequivalence was assessed by standard noncompartmental methods. Ibuprofen plasma concentrations were fitted with a model that took bioinversion of R- to S-ibuprofen into account. Results, Peak plasma concentrations of R- and S-ibuprofen were 18.1 and 20 µg ml,1 (test), and 18.2 and 20 µg ml,1 (reference). Areas under the plasma concentration vs time curves were 39.7 and 67.5 µg ml,1 h (test), and 41.1 and 68.2 µg ml,1 h (reference). Clearance of R-ibuprofen was 5.2 (test) and 5 l h,1 (reference). A specific plasma concentration was reached with the test formulation about 5 min later than with the reference. Parameters from compartmental modelling were (given for R-and then for S-ibuprofen): body clearance: 4.9 and 4.64 l h,1, central volume of distribution: 2.8 and 4.1 l, intercompartment clearance: 5.1 and 5.45 l h,1, peripheral volume of distribution: 4.1 and 5.2 l. The absorption rate constant was 1.52 h,1, and the test but not the reference formulation had a lag time of 0.1 h. Simulations showed similarity between formulations of the expected effects except for a calculated delay of 6 min with the test formulation. Conclusions, Ibuprofen formulations were bioequivalent. The pharmacokinetic model may serve as a basis for future pharmacokinetic/pharmacodynamic calculations after administration of racemic ibuprofen. [source] Pharmacokinetics and pharmacodynamics of NTBC (2-(2-nitro-4-fluoromethylbenzoyl)-1,3-cyclohexanedione) and mesotrione, inhibitors of 4-hydroxyphenyl pyruvate dioxygenase (HPPD) following a single dose to healthy male volunteersBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 2 2001Michael G. Hall Aims NTBC (2-(2-nitro-4-fluoromethylbenzoyl)-1,3-cyclohexanedione) and mesotrione (2-(4-methylsulphonyl-2-nitrobenzoyl)-1,3-cyclohexanedione) are inhibitors of 4-hydroxyphenyl pyruvate dioxygenase (HPPD). NTBC has been successfully used as a treatment for hereditary tyrosinaemia type 1 (HT-1), while mesotrione has been developed as an herbicide. The pharmacokinetics of the two compounds were investigated in healthy male volunteers following single oral administration. The aim of the NTBC study was to assess the bioequivalence of two different formulations and to determine the extent of the induced tyrosinaemia. The mesotrione study was performed to determine the magnitude and duration of the effect on tyrosine catabolism. Additionally, the urinary excretion of unchanged mesotrione was measured to assess the importance of this route of clearance and to help develop a strategy for monitoring occupational exposure. Methods A total of 28 volunteers participated in two separate studies with the compounds. In the first study, the relative bioavailability of NTBC from liquid and capsule formulations was compared and the effect on plasma tyrosine concentrations measured. In the second study the pharmacokinetics of mesotrione were determined at three doses. Plasma tyrosine concentrations were monitored and the urinary excretion of mesotrione and tyrosine metabolites was measured. Results Both compounds were well tolerated at the dose levels studied. Peak plasma concentrations of NTBC were rapidly attained following a single oral dose of 1 mg kg,1 body weight of either formulation and the half-life in plasma was approximately 54 h. There were no statistical differences in mean (± s.d.) AUC(0,,) (capsule 602 ± 154 vs solution 602 ± 146 µg ml,1 h) or t½ (capsule 55 ± 13 vs solution 54 ± 8 h) and these parameters supported the bioequivalence of the two formulations. Mesotrione was also rapidly absorbed, with a significant proportion of the dose eliminated unchanged in urine. The plasma half-life was approximately 1 h and was independent of dose and AUC(0,,) and Cmax increased linearly with dose. Following administration of 1 mg NTBC kg,1 in either formulation, the concentrations of tyrosine in plasma increased to approximately 1100 nmol ml,1. Concentrations were still approximately 8 times those of background at 14 days after dosing, but had returned to background levels within 2 months of the second dose. Administration of mesotrione resulted in an increase in tyrosine concentrations which reached a maximum of approximately 300 nmol ml,1 following a dose of 4 mg kg,1 body weight. Concentrations returned to those of background within 2 days of dosing. Urinary excretion of tyrosine metabolites was increased during the 24 h immediately following a dose of 4 mg mesotrione kg,1, but returned to background levels during the following 24 h period. Conclusions NTBC and mesotrione are both inhibitors of HPPD, although the magnitude and duration of their effect on tyrosine concentrations are very different. When normalized for dose, the extent of the induced tyrosinaemia after administration of NTBC and over the duration of these studies, was approximately 400 fold greater than that following administration of mesotrione. The persistent and significant effect on HPPD following administration of NTBC make it suitable for the treatment of patients with hereditary tyrosinaemia type 1 (HT-1), whilst the minimal and transient effects of mesotrione minimize the likelihood of a clinical effect in the event of systemic exposure occurring during occupational use. [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] Effects of myricetin, an antioxidant, on the pharmacokinetics of losartan and its active metabolite, EXP-3174, in rats: possible role of cytochrome P450 3A4, cytochrome P450 2C9 and P-glycoprotein inhibition by myricetinJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 7 2010Dong-Hyun Choi Abstract Objectives, The effects of myricetin, a natural flavonoid, on the pharmacokinetics of losartan and its active metabolite, EXP-3174, were investigated in rats. Losartan and myricetin interact with cytochrome P450 (CYP) enzymes and P-glycoprotein, and the increase in the use of health supplements may result in myricetin being taken concomitantly with losartan as a combination therapy to treat or prevent cardiovascular diseases. Methods, The pharmacokinetic parameters of losartan and EXP-3174 were determined after oral administration of losartan (9 mg/kg) to rats in the presence or absence of myricetin (0.4, 2 and 8 mg/kg). The effects of myricetin on P-glycoprotein as well as CYP3A4 and CYP2C9 activity were also evaluated. Key findings, Myricetin inhibited CYP3A4 and CYP2C9 enzyme activity with a 50% inhibition concentration of 7.8 and 13.5 µm, respectively. In addition, myricetin significantly enhanced the cellular accumulation of rhodamine 123 in MCF-7/ADR cells overexpressing P-glycoprotein in a concentration-dependent manner. The pharmacokinetic parameters of losartan were significantly altered by myricetin compared with the control. The presence of myricetin (2 or 8 mg/kg) increased the area under the plasma concentration,time curve of losartan by 31.4,61.1% and peak plasma concentration of losartan by 31.8,50.2%. Consequently, the absolute bioavailability of losartan in the presence of myricetin increased significantly (P < 0.05, 2 mg/kg; P < 0.01, 8 mg/kg) compared with the control. There was no significant change in the time to reach the peak plasma concentration, apparent volume of distribution at steady state or terminal half-life of losartan in the presence of myricetin. Furthermore, concurrent use of myricetin (8 mg/kg) significantly decreased the metabolite,parent area under the plasma concentration,time curve ratio by 20%, implying that myricetin may inhibit the CYP-mediated metabolism of losartan to its active metabolite, EXP-3174. Conclusions, The enhanced bioavailability of losartan may be mainly due to inhibition of the CYP3A4- and CYP2C9-mediated metabolism of losartan in the small intestine or in the liver, and the P-glycoprotein efflux pump in the small intestine by myricetin. [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] Selected pharmacokinetic parameters for Cefovecin in hens and green iguanasJOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 6 2009L. R. THUESEN The third generation cephalosporin cefovecin has been shown to have an exceptionally long elimination half-life in dogs and cats, making it suitable for antibacterial treatment with a 14-day dosing interval in these species. Pharmacokinetic parameters for cefovecin were investigated in juvenile hens and green iguanas, following subcutaneous injections with 10 mg cefovecin/kg bodyweight. Preliminary studies in eight additional species of birds and reptiles were performed and results were compared with the parameters found in hens and green iguanas. The kinetics were characterized by rapid absorption with peak plasma concentration of 6 ± 2 ,g/mL in hens and 35 ± 12 ,g/mL in green iguanas. The mean plasma half-life for cefovecin was 0.9 ± 0.3 h for hens and 3.9 h in green iguanas. Volume of distribution was 1.6 ± 0.5 L/kg for hens and 0.3 L/kg for green iguanas and clearance was 1252 ± 185 mL·h/kg for hens and 53 mL·h/kg for green iguanas. Results from preliminary studies did not differ notably from those seen in hens and green iguanas. Cefovecin is not suitable for the treatment of bacterial infections with a 14-day dosing interval in hens or green iguanas and seems not to be in a number of other bird and retile species either. [source] Pharmacokinetics of the calcium-channel blocker diltiazem after a single intravenous dose in horses,JOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 3 2006C. C. SCHWARZWALD The pharmacokinetics of diltiazem were determined in eight healthy horses. Diltiazem HCl, 1 mg/kg i.v., was administered over 5 min. Venous blood samples were collected at regular intervals after administration. Plasma concentrations of diltiazem and desacetyldiltiazem were determined by high-performance liquid chromatography. A second, putative metabolite was detected, but could not be identified due to the lack of an authentic standard. Data were analyzed by nonlinear least-squares regression analysis. The median (minimum,maximum) peak plasma concentration of diltiazem was 727 (539,976) ng/mL. Plasma diltiazem concentration vs. time data were best described by a two-compartment model with first-order drug elimination. The distribution half-life was 12 (6,23) min, the terminal half-life was 93 (73,161) min, the mean residence time was 125 (99,206) min, total plasma clearance was 14.4 (10.4,18.6) mL/kg/min, and the volume of distribution at steady-state was 1.84 (1.46,2.51) L/kg. The normalized ratio of the area under the curve (AUC) of desacetyldiltiazem to the AUC of diltiazem was 0.088 (0.062,0.179). The disposition of diltiazem in horses was characterized by rapid distribution and elimination and a terminal half-life shorter than reported in humans and dogs. Because of the reported low pharmacologic activity, plasma diltiazem metabolite concentrations were not considered clinically important. [source] Grapefruit Juice Enhances the Exposure to Oral OxycodoneBASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 4 2010Tuija H. Nieminen The objective of this study was to examine the effect of grapefruit juice on the pharmacokinetics and pharmacodynamics of oral oxycodone in a randomized cross-over study with two phases at an interval of 4 weeks. Twelve healthy volunteers ingested 200 ml of grapefruit juice or water t.i.d. for 5 days. An oral dose of oxycodone hydrochloride 10 mg was administered on day 4. Oxycodone, noroxycodone, oxymorphone and noroxymorphone concentrations were analysed from the plasma samples for 48 hr and behavioural and analgesic effects were recorded for 12 hr. Grapefruit juice increased the mean area under the oxycodone concentration,time curve (AUC0,,) by 1.7-fold (p < 0.001), the peak plasma concentration by 1.5-fold (p < 0.001) and the half-life of oxycodone by 1.2-fold (p < 0.001) as compared to the water. The metabolite-to-parent AUC0,, ratios (AUCm/AUCp) of noroxycodone and noroxymorphone decreased by 44% (p < 0.001) and 45% (p < 0.001), respectively. Oxymorphone AUC0,, increased by 1.6-fold (p < 0.01) after grapefruit juice, but the AUCm/AUCp remained unchanged. Pharmacodynamic changes were modest and only self-reported performance significantly impaired after grapefruit juice. Analgesic effects were not influenced. Grapefruit juice inhibited the CYP3A4-mediated first-pass metabolism of oxycodone, decreased the formation of noroxycodone and noroxymorphone and increased that of oxymorphone. We conclude that dietary consumption of grapefruit products may increase the concentrations and effects of oxycodone in clinical use. [source] A sensitive method for determination of salvianolic acid A in rat plasma using liquid chromatography/tandem mass spectrometryBIOMEDICAL CHROMATOGRAPHY, Issue 7 2008Lixia Pei Abstract Salvianolic acid A (SAA), a major effective constituent of Salvia miltiorrhizas, is widely used in traditional Chinese medicine. A sensitive rapid analytical method was established and validated for SAA in rat plasma, which was further applied to assess the pharmacokinetics of SAA in rats receiving a single oral dose of SAA. The method used liquid chromatography tandem mass spectrometry in multiple reaction monitoring mode with chloramphenicol as the internal standard. A simple liquid,liquid extraction based on ethyl acetate was employed. The combination of a simple sample cleanup and short chromatographic run time (3 min) increased the throughput of the method substantially. The method was validated over the range 1.4,1000 ng/mL with a correlation coefficient >0.99. The lower limit of quantification was 1.4 ng/mL for SAA in plasma. Intra- and inter-day accuracies for SAA were 95,113 and 98,107%, and the inter-day precision was less than 12%. This method is more sensitive and faster than previous methods. After a single oral dose of 100 mg/kg of SAA, the mean peak plasma concentration (Cmax) of SAA was 318 ng/mL at 0.5 h, the area under the plasma concentration,time curve (AUC0,12 h) was 698 ± 129 ng·h/mL, and the elimination half-life (T1/2) was 3.29 h. Copyright © 2008 John Wiley & Sons, Ltd. [source] Bioavailability of modified-release methylphenidate: influence of high-fat breakfast when administered intact and when capsule content sprinkled on applesauceBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 6 2003Lucy Lee Abstract Ritalin®, an immediate release form of racemic methylphenidate hydrochloride, has been available in the USA since 1955 and is used for the treatment of ADHD. The objective of this study was to evaluate the pharmacokinetics of modified-release methylphenidate (highest single dose), Ritalin® LA, when administered under fasting condition, with a high-fat breakfast, and when sprinkled on applesauce in healthy adult subjects. Blood samples were drawn for 24 h following a 40 mg oral administration. Most subjects appeared to produce a bimodal methylphenidate plasma concentration profile. In all three treatment groups, methylphenidate was rapidly absorbed with an initial average tmax(0,4) of 1.3,2.4 h and an average peak plasma concentration [Cmax(abs)] of 14.4,15.2 ng/ml. On average, both the rate [Cmax(abs) and tmax(abs)] and the extent of absorption (AUC0,,) of methylphenidate were similar when the capsule was given with a high fat breakfast and when the capsule contents were sprinkled onto applesauce, compared with the fasting state. No dose dumping was observed when the capsule was given with a high fat breakfast or when sprinkled onto applesauce. The dose was safe and generally well tolerated. Coadministration of a single oral dose of 40 mg methylphenidate capsule whether administered intact with a high-fat breakfast or sprinkled on applesauce did not affect the overall rate or extent of absorption of methylphenidate compared with the fasted condition. Copyright © 2003 John Wiley & Sons, Ltd. [source] Pharmacokinetics and dose proportionality of BMS-204352 after intraarterial administration to ratsBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 6 2002Rajesh Krishna Abstract BMS-204352 is a novel maxi-K channel opener that is being developed for the treatment for stroke. The current study was designed to evaluate the dose proportionality and pharmacokinetics of BMS-204352 in rats. In an open, parallel fashion, sixteen rats per gender received a single intraarterial dose of BMS-204352 as a 3-min infusion into the carotid artery at 0.4, 2.0, 5.0 and 10.0 mg/kg dose levels. Serial blood samples were collected for up to 24 h post-dose and plasma samples were analyzed for the concentrations of intact BMS-204352 using a validated liquid chromatographic mass spectrometric (LC/MS) method. Pharmacokinetic analysis was performed using a non-compartmental method. Results revealed a gender difference in the pharmacokinetics of BMS-204352 in rats at all doses excluding the first (i.e., 0.4 mg/kg) dose panel. BMS-204352 peak plasma concentration (Cmax) and area under the plasma concentration,time curve (AUC) values increased in a proportion greater than the increment in dose. Specifically, as dose increased in the ratio 1:5:12.5:25, Cmax increased in the ratio 1:7:18:31 in male rats and 1:7:22:51 in female rats. The respective AUC ratios were 1:6:20:42 in male rats and 1:12:29:77 in female rats. Mean total body clearance (CLT) values for BMS-204352 ranged from 879,3242 ml/h/kg over the four dose levels and generally decreased with increase in dose. Similarly, steady state volume of distribution (VSS) values ranged from 3621,8933 ml/kg over the four dose levels and generally decreased with increase in dose. However, mean residence time (MRT) and elimination half-life (T1/2) values for BMS-204352 were independent of dose and ranged from 2.42,4.54 to 2.08,4.70 h, respectively. In conclusion, BMS-204352 appears to exhibit dose-dependent pharmacokinetics in rats. In addition, there appeared to be some evidence of gender related differences in the pharmacokinetics of BMS-204352. Copyright © 2002 John Wiley & Sons, Ltd. [source] Subacute toxicities and toxicokinetics of a new erectogenic, DA-8159, after single and 4-week repeated oral administration in dogsBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 3 2001Hyun J. Shim Abstract The subacute toxicities and toxicokinetics of a new erectogenic, DA-8159, were evaluated after single (at the 1st day) and 4-week (at the 28th day) oral administration of the drug, in doses of 0 (to serve as a control), 12.5, 50 and 200 mg/kg/day, to male and female dogs (n=3 for male and female dogs for each dose). DA-8159 had an effect on the immune-related organs (or tissues), circulatory systems, liver, adrenal glands, ovaries and pancreas. The toxic dose was 200 mg/kg and no observed adverse effect level was less than 50 mg/kg for male and female dogs. There were no significant gender differences in the pharmacokinetic parameters of DA-8159 for each dose after both single and 4-week oral administration. The pharmacokinetic parameters of DA-8159 were dose-independent after single oral administration; the time to reach a peak plasma concentration (Tmax) and the dose-normalized area under the plasma concentration,time curve from time zero to 24 h in plasma (AUC0,24 h) were not significantly different among three doses. However, accumulation of DA-8159 after 4-week oral administration was considerable at toxic dose, 200 mg/kg/day. For example, after 4-week administration, the dose-normalized AUC0,24 h value at 200 mg/kg/day (4.71 and 15.3 ,g h/ml) was significantly greater than that at 12.5 mg/kg/day. After 4-week oral administration, the dose-normalized Cmax and AUC0,24 h at 200 mg/kg/day were significantly higher and greater, respectively, than those after a single oral administration. Copyright © 2001 John Wiley & Sons, Ltd. [source] Effect of multiple doses of montelukast on the pharmacokinetics of rosiglitazone, a CYP2C8 substrate, in humansBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 3 2007Kyoung-Ah Kim Aims To investigate the effect of multiple dosing with montelukast, a selective leukotriene-receptor antagonist, on the pharmacokinetics of rosiglitazone, a CYP2C8 substrate, in humans. Methods A two-period, randomized crossover study was conducted in 10 healthy subjects. After administration of oral doses of placebo or 10 mg montelukast daily for 6 days, 4 mg rosiglitazone was administered and plasma samples were obtained for 24 h and analyzed for rosiglitazone and N-desmethylrosiglitazone using high-performance liquid chromatography with fluorescence detection. Results During the montelukast phase, the total area under the time-concentration curve (AUC) and peak plasma concentration of rosiglitazone were 102% (90% CI 98, 107%) and 98% (90% CI 92, 103%) of the corresponding values during the placebo phase, respectively. Multiple dosing with montelukast did not affect the oral clearance of rosiglitazone significantly (90% CI 94, 105%; P = 0.50). The AUC ratio and plasma concentration ratios of N-desmethylrosiglitazone : rosiglitazone were not changed by multiple dosing with montelukast (90% CI 90, 103%; P = 0.14). Conclusions Multiple doses of montelukast do not inhibit CYP2C8-mediated rosiglitazone metabolism in vivo despite in vitro findings indicating that montelukast is a selective CYP2C8 inhibitor. [source] Rofecoxib is a potent inhibitor of cytochrome P450 1A2: studies with tizanidine and caffeine in healthy subjectsBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 3 2006Janne T. Backman Aims Case reports suggest an interaction between rofecoxib and the CYP1A2 substrate tizanidine. Our objectives were to explore the extent and mechanism of this possible interaction and to determine the CYP1A2 inhibitory potency of rofecoxib. Methods In a randomized, double-blind, two-phase cross-over study, nine healthy subjects took 25 mg rofecoxib or placebo daily for 4 days and, on day 4, each ingested 4 mg tizanidine. Plasma concentrations and the urinary excretion of tizanidine, its metabolites (M) and rofecoxib, and pharmacodynamic variables were measured up to 24 h. On day 3, a caffeine test was performed to estimate CYP1A2 activity. Results Rofecoxib increased the area under the plasma concentration,time curve (AUC0,,) of tizanidine by 13.6-fold [95% confidence interval (CI) 8.0, 15.6; P < 0.001), peak plasma concentration (Cmax) by 6.1-fold (4.8, 7.3; P < 0.001) and elimination half-life (t1/2) from 1.6 to 3.0 h (P < 0.001). Consequently, rofecoxib markedly increased the blood pressure-lowering and sedative effects of tizanidine (P < 0.05). Rofecoxib increased several fold the tizanidine/M-3 and tizanidine/M-4 ratios in plasma and urine and the tizanidine/M-5, tizanidine/M-9 and tizanidine/M-10 ratios in urine (P < 0.05). In addition, it increased the plasma caffeine/paraxanthine ratio by 2.4-fold (95% CI 1.4, 3.4; P = 0.008) and this ratio correlated with the tizanidine/metabolite ratios. Finally, the AUC0,25 of rofecoxib correlated with the placebo phase caffeine/paraxanthine ratio (r = 0.80, P = 0.01). Conclusions Rofecoxib is a potent inhibitor of CYP1A2 and it greatly increases the plasma concentrations and adverse effects of tizanidine. The findings suggest that rofecoxib itself is also metabolized by CYP1A2, raising concerns about interactions between rofecoxib and other CYP1A2 substrate and inhibitor drugs. [source] Pharmacokinetics of detomidine administered to horses at rest and after maximal exerciseEQUINE VETERINARY JOURNAL, Issue 5 2009J. A. E. HUBBELL Summary Reason for performing study: Increased doses of detomidine are required to produce sedation in horses after maximal exercise compared to calm or resting horses. Objectives: To determine if the pharmacokinetics of detomidine in Thoroughbred horses are different when the drug is given during recuperation from a brief period of maximal exercise compared to administration at rest. Methods: Six Thoroughbred horses were preconditioned by exercising them on a treadmill. Each horse ran a simulated race at a treadmill speed that caused it to exercise at 120% of its maximal oxygen consumption. One minute after the end of exercise, horses were treated with detomidine. Each horse was treated with the same dose of detomidine on a second occasion a minimum of 14 days later while standing in a stocks. Samples of heparinised blood were obtained at various time points on both occasions. Plasma detomidine concentrations were determined by liquid chromatographymass spectrometry. The plasma concentration vs. time data were analysed by nonlinear regression analysis. Results: Median back-extrapolated time zero plasma concentration was significantly lower and median plasma half-life and median mean residence time were significantly longer when detomidine was administered after exercise compared to administration at rest. Median volume of distribution was significantly higher after exercise but median plasma clearance was not different between the 2 administrations. Conclusions and potential relevance: Detomidine i.v. is more widely distributed when administered to horses immediately after exercise compared to administration at rest resulting in lower peak plasma concentrations and a slower rate of elimination. The dose requirement to produce an equivalent effect may be higher in horses after exercise than in resting horses and less frequent subsequent doses may be required to produce a sustained effect. [source] BRIEF COMMUNICATIONS: A quantity survey of intravenous administration of metronidazole in its different forms in a tertiary teaching hospitalINTERNAL MEDICINE JOURNAL, Issue 8 2010L. L. Lee Abstract The aim of this paper is to examine the prescribing patterns and cost of various formulations of metronidazole in a hospital setting over a 3-month period. Oral metronidazole has high bioavailability (98.9%) with peak plasma concentrations averaged at 2.3 h after dosing. Despite the high bioavailability of oral metronidazole, many patients continue to receive metronidazole intravenously when they are suitable for oral preparation. An audit of 120 consecutive patients prescribed metronidazole was conducted at the Liverpool Hospital, NSW, from March to July 2005. There were 65 men and 55 women (age 18,93). Of the 120 patients, 16 were on oral, 1 on rectal and 103 were on intravenous metronidazole. Treatment was initiated based on clinical diagnoses. Potential pathogens were subsequently identified on only 21 occasions. The use of metronidazole as an oral preparation was contraindicated in 27 patients (22.5%) who were nil-by-mouth. Of these, rectally administered metronidazole was contraindicated in only eight patients. The average course of intravenous metronidazole was 8.0 ± 9.7 days (mean ± SD). The total number of intravenous metronidazole treatment days was 824. Oral metronidazole would have been possible in 618 out of the 824 days. The estimated cost to administer each dose of oral, suppository and intravenous forms of metronidazole is $A0.11, $A1.34 and $A6.09 respectively. Thus, substantial savings could be achieved if oral metronidazole were to be administered whenever possible. The early use of oral or rectal metronidazole should be encouraged when there are no clinical contraindications. [source] The pharmacokinetics and pharmacodynamics of alfaxalone in cats after single and multiple intravenous administration of Alfaxan® at clinical and supraclinical dosesJOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 6 2008T. WHITTEM This study aimed to determine the pharmacokinetic parameters and pharmacodynamics of alfaxalone in a 2-hydroxypropyl-,-cyclodextrin alfaxalone formulation (Alfaxan®, Jurox Pty Ltd, Rutherford, NSW, Australia) in cats after single administration at clinical and supraclinical dose rates and as multiple maintenance doses. First, a prospective two-period cross-over study was conducted at single clinical and supraclinical doses. Second, a single group multiple dose study evaluated the effect of maintenance doses. Eight (five female and three male) domestic cats completed the cross-over experiment and six female cats completed the multiple dose study. In the first experiment, alfaxalone was administered intravenously (IV) at 5 or 25 mg/kg with a washout period of 14 days. In the second experiment, alfaxalone was administered IV at 5 mg/kg followed by four doses each of 2 mg/kg, administered at onset of responsiveness to a noxious stimulus. Blood was collected at prescribed intervals and analysed by LCMS for plasma alfaxalone concentration. Noncompartmental pharmacokinetics were used to analyse the plasma alfaxalone data. The plasma clearance of alfaxalone at 5 and 25 mg/kg differed statistically at 25.1 and 14.8 mL/kg/min respectively. The elimination half lives were 45.2 and 76.6 min respectively. Alfaxalone has nonlinear pharmacokinetics in the cat. Nevertheless, for cats dosed with sequential maintenance doses, a regression line through their peak plasma concentrations indicated that there was no clinically relevant pharmacokinetic accumulation. The duration of nonresponsiveness after each maintenance dose was similar at approximately 6 min, indicating a lack of accumulation of pharmacodynamic effect. The cardiovascular and respiratory parameters measured in cats after administration of the labelled doses of Alfaxan® were stable. In conclusion, the pharmacokinetics of alfaxalone in cats are nonlinear. At clinical dose rates, however, neither alfaxalone nor its effects accumulated to a clinically relevant extent. Further, in the un-premedicated cat the induction and maintenance of surgical anaesthesia was free of untoward events after a dose of 5 mg alfaxalone/kg body weight followed by four sequential doses of 2 mg/kg as needed (i.e., approximately 7 to 8 mg/kg/h). [source] Pharmacokinetics of difloxacin in pigs and broilers following intravenous, intramuscular, and oral single-dose applicationsJOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 3 2008H. Z. DING Pharmacokinetics of difloxacin, a fluoroquinolone antibiotic, was determined in pigs and broilers after intravenous (i.v.), intramuscular (i.m.), or oral (p.o.) administration at a single dose of five (pigs) or 10 mg/kg (broilers). Plasma concentration profiles were analyzed by a compartmental pharmacokinetic method. Following i.v., i.m. and p.o. doses, the elimination half-lives (t1/2,) were 17.14 ± 4.14, 25.79 ± 8.10, 16.67 ± 4.04 (pigs) and 6.11 ± 1.50, 5.64 ± 0.74, 8.20 ± 3.12 h (broilers), respectively. After single i.m. and p.o. administration, difloxacin was rapidly absorbed, with peak plasma concentrations (Cmax) of 1.77 ± 0.66, 2.29 ± 0.85 (pigs) and 2.51 ± 0.36, 1.00 ± 0.21 ,g/mL (broilers) attained at tmax of 1.29 ± 0.26, 1.41 ± 0.88 (pigs) and 0.86 ± 0.4, 4.34 ± 2.40 h (broilers), respectively. Bioavailabilities (F) were (95.3 ± 28.9)% and (105.7 ± 37.1)% (pigs) and (77.0 ± 11.8)% and (54.2 ± 12.6)% (broilers) after i.m. and p.o. doses, respectively. Apparent distribution volumes(Vd(area)) of 4.91 ± 1.88 and 3.10 ± 0.67 L/kg and total body clearances(ClB) of 0.20 ± 0.06 and 0.37 ± 0.10 L/kg/h were determined in pigs and broilers, respectively. Areas under the curve (AUC), the half-lives of both absorption and distribution(t1/2ka, t1/2,) were also determined. Based on the single-dose pharmacokinetic parameters determined, multiple dosage regimens were recommended as: a dosage of 5 mg/kg given intramuscularly every 24 h in pigs, or administered orally every 24 h at the dosage of 10 mg/kg in broilers, can maintain effective plasma concentrations with bacteria infections, in which MIC90 are <0.25 ,g/mL and <0.1 ,g/mL respectively. [source] Inhibitory Effects of Silibinin on Cytochrome P-450 Enzymes in Human Liver MicrosomesBASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 6 2000Svane Beckmann-Knopp Silibinin, the main constituent of silymarin, a flavonoid drug from silybum marianum used in liver disease, was tested for inhibition of human cytochrome P-450 enzymes. Metabolic activities were determined in liver microsomes from two donors using selective substrates. With each substrate, incubations were carried out with and without silibinin (concentrations 3.7,300 ,M) at 37° in 0.1 M KH2PO4 buffer containing up to 3% DMSO. Metabolite concentrations were determined by HPLC or direct spectroscopy. First, silibinin IC50 values were determined for each substrate at respective KM concentrations. Silibinin had little effect (IC50>200 ,M) on the metabolism of erythromycin (CYP3A4), chlorzoxazone (CYP2E1), S(+)-mephenytoin (CYP2C19), caffeine (CYP1A2) or coumarin (CYP2A6). A moderate effect was observed for high affinity dextromethorphan metabolism (CYP2D6) in one of the microsomes samples tested only (IC50=173 ,M). Clear inhibition was found for denitronifedipine oxidation (CYP3A4; IC50=29 ,M and 46 ,M) and S(,)-warfarin 7-hydroxylation (CYP2C9; IC50=43 ,M and 45 ,M). When additional substrate concentrations were tested to assess enzyme kinetics, silibinin was a potent competitive inhibitor of dextromethorphan metabolism at the low affinity site, which is not CYP2D6 (Ki,c=2.3 ,M and 2.4 ,M). Inhibition was competitive for S(,)-warfarin 7-hydroxylation (Ki,c=18 ,M and 19 ,M) and mainly non-competitive for denitronifedipine oxidation (Ki,n=9 ,M and 12 ,M). With therapeutic silibinin peak plasma concentrations of 0.6 ,M and biliary concentrations up to 200 ,M, metabolic interactions with xenobiotics metabolised by CYP3A4 or CYP2C9 cannot be excluded. [source] Pharmacokinetic interaction between fluoxetine and metoclopramide in healthy volunteersBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 6 2006Laurian Vlase Abstract The pharmacokinetic interaction of fluoxetine with metoclopramide in healthy volunteers was evaluated. A dose of 20 mg metoclopramide in combination with 60 mg fluoxetine was administered to 24 healthy male volunteers in a two treatment study design, separated by 8 days in which the fluoxetine alone was administered as a single p.o. dose daily. Plasma concentrations of metoclopramide were determined during a 24 h period following drug administration. Metoclopramide plasma concentrations were determined by a validated HPLC method. Pharmacokinetic parameters of metoclopramide were calculated using non-compartmental analysis. In the two periods of treatment, the mean peak plasma concentrations (Cmax) were 44.02 ng/ml (metoclopramide alone) and 62.72 ng/ml (metoclopramide after pre-treatment with fluoxetine). The times taken to reach Cmax and tmax, were 1.15 h and 1.06 h, respectively. The total areas under the curve (AUC0,,) were 312.61 ng.h/ml and 590.62 ng.h/ml, respectively. The half-life values (t1/2) were 5.52 h and 8.47 h. Statistically significant differences were observed for both AUC0,, and t1/2 of metoclopramide when administered alone or after 8 days treatment with fluoxetine. The experimental data demonstrate the pharmacokinetic interaction between fluoxetine and metoclopramide and suggest that the observed interaction may be clinically significant, but its relevance has to be confirmed. Copyright © 2006 John Wiley & Sons, Ltd. [source] The pharmacokinetics, pharmacodynamics and tolerability of dabigatran etexilate, a new oral direct thrombin inhibitor, in healthy male subjectsBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 3 2007Joachim Stangier Aims The novel direct thrombin inhibitor (DTI), dabigatran etexilate (Boehringer Ingelheim Pharma GmbH & Co. KG), shows potential as an oral antithrombotic agent. Two double-blind, randomized trials were undertaken to investigate the pharmacokinetics (PK), pharmacodynamics (PD) and tolerability of orally administered dabigatran etexilate in healthy male subjects. Methods Dabigatran etexilate or placebo was administered orally at single doses of 10,400 mg (n = 40) or at multiple doses of 50,400 mg three times daily for 6 days (n = 40). Plasma and urine samples were collected over time to determine the PK profile of dabigatran. PD activity was assessed by its effects on blood coagulation parameters: activated partial thromboplastin time (aPTT), prothrombin time (PT), reported as international normalized ratio (INR), thrombin time (TT), and ecarin clotting time (ECT). All adverse events were recorded. Results Dabigatran etexilate was rapidly absorbed with peak plasma concentrations of dabigatran reached within 2 h of administration. This was followed by a rapid distribution/elimination phase and a terminal phase, with associated estimated half-lives of 8,10 h and 14,17 h with single and multiple dose administrations, respectively. Dabigatran exhibited linear PK characteristics with dose-proportional increases observed in maximum plasma concentration and area under the curve. Steady-state conditions were reached within 3 days with multiple dosing. The mean apparent volume of distribution during the terminal phase (Vz/F) of 1860 l (range 1430,2400 l) and the apparent total clearance after oral administration (CLtot/F) of 2031 ml min,1 (range 1480,2430), were dose independent. Time curves for aPTT, INR, TT and ECT paralleled plasma concentration,time curves with values increasing rapidly and in a dose-dependent manner. At the highest dose of 400 mg administered three times daily, maximum prolongations over baseline of 3.1 (aPTT), 3.5 (INR), 29 (TT) and 9.5-fold (ECT) were observed. Dabigatran underwent conjugation with glucuronic acid to form pharmacologically active conjugates that accounted for approximately 20% of total dabigatran in plasma. Overall, variability in PK parameters was low to moderate, with an average interindividual coefficient of variation (CV) of approximately 30% and variability in PD parameters was low, with CV < 10%. Of the four assays, TT and ECT exhibited the greatest sensitivity and precision within the anticipated therapeutic dose range. Bleeding events were few and were mild-to-moderate in intensity, occurring only in the higher, multiple dose groups. Conclusions These data suggest that dabigatran etexilate is a promising novel oral DTI with predictable PK and PD characteristics and good tolerability. Further investigation of dabigatran etexilate for the treatment and prophylaxis of patients with arterial and venous thromboembolic disorders, acute coronary syndromes and other medical conditions is warranted. [source] | |||||||||||||||||||||||||