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Plasma Clearance (plasma + clearance)
Selected AbstractsPlasma Clearance of Exogenous Creatinine, Exo-Iohexol, and Endo-Iohexol in Hyperthyroid Cats before and after Treatment with RadioiodineJOURNAL OF VETERINARY INTERNAL MEDICINE, Issue 4 2008I. Van Hoek Background: Glomerular filtration rate (GFR) can be measured by clearance methods of different markers showing discrepancies and different reproducibility in healthy cats. Studies comparing different methods of GFR measurement in hyperthyroid cats have not yet been performed. Hypothesis: Plasma clearance of exogenous creatinine (PECCT), exo-iohexol (PexICT), and endo-iohexol (PenICT) could lead to differences in GFR measurement and the need to use the same clearance method when comparing GFR before and after radioiodine treatment in hyperthyroid cats. Animals: Fifteen client-owned hyperthyroid cats. Methods: GFR was measured 1 day before and 1, 4, 12, and 24 weeks after treatment. Intravenous injection of iohexol was followed immediately by IV injection of creatinine. Plasma creatinine was measured by an enzymatic method. Plasma endo- and exo-iohexol were measured by high-performance liquid chromatography coupled to ultraviolet detection. Results: Globally, the 3 GFR methods resulted in significantly different (P < .001) GFR results. GFR results among the different methods were the same (P= .999) at all time points. All 3 techniques indicated decreasing GFR after 131I treatment. For each GFR technique, a significant decrease in GFR was observed between time point 0 and all other time points. This decrease stabilized 4 weeks after treatment, with very little decline afterward. Conclusion and Clinical Importance: It is mandatory to use the same GFR technique in follow-up studies. GFR testing at 4 weeks posttreatment could allow assessment of the final renal functional loss after treatment in hyperthyroid cats. [source] Pharmacokinetic and pharmacodynamic properties of metomidate in turbot (Scophthalmus maximus) and halibut (Hippoglossus hippoglossus)JOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 2 2003M. K. Hansen Metomidate was administered to halibut (Hippoglossus hippoglossus) and turbot (Scophthalmus maximus) intravenously at a dose of 3 mg/kg bodyweight, as a bath treatment at a dose of 9 mg/L water for 5 min to study the disposition of metomidate, and as bath treatment (9 mg/L) for 10 min to study the absorption and effect of metomidate on respiration and balance/motor control. Additionally, turbot were given metomidate orally at a dose of 7 mg/kg. The studies were performed in seawater at a temperature of 10.3 ± 0.4 °C (halibut) and 18.0 ± 0.3 °C (turbot). Pharmacokinetic modeling of the data showed that metomidate had shorter elimination half-life and higher plasma concentrations in turbot compared with halibut, both species displaying a rapid uptake, distribution and excretion. Following intravenous administration, the volumes of distribution at steady state (Vd(ss)) were 0.21 L/kg (halibut) and 0.44 L/kg (turbot). Plasma clearances (Cl) were 0.099 L/h·kg in halibut and 0.26 L/h·kg in turbot and the elimination half-lives (t½,z) were calculated to be 5.8 h and 2.2 h in halibut and turbot, respectively. Mean residence times (MRT) were 2.2 h in halibut and 1.7 h in turbot. Following oral administration, the t½,z was 3.5 h in turbot. The maximum plasma concentration (Cmax) was 7.8 mg/L in turbot 1 h after administration. The oral bioavailability (F) was calculated to 100% in turbot. Following 5 min bath the maximum plasma concentrations (Cmax), which were observed immediately after end of the bath, were 9.5 mg/L and 13.3 mg/L in halibut and turbot, respectively. Metomidate rapidly immobilized the fish, with respiratory depression, reduced heart rate, and loss of balance/motor control within 1 min (mean). Recovery was slow, with resumed balance/motor control after 26.4 min. Opercular respiration movements were resumed more rapidly with a recorded mean of 1.7 min. Oral administration was demonstrated to be a way of immobilizing fish, for example in large aquariums, without exposing them to unwanted stress. [source] The accuracy of cystatin C and commonly used creatinine-based methods for detecting moderate and mild chronic kidney disease in diabetesDIABETIC MEDICINE, Issue 4 2007R. J. MacIsaac Abstract Background, The accuracy of measuring serum cystatin C levels for detecting various stages of chronic kidney disease (CKD) in diabetes is still unclear. Methods In a cross-sectional study of 251 subjects, a reference glomerular filtration rate (GFR) was measured using 99cTc-DTPA plasma clearance (iGFR). Multivariate analysis was used to identify independent clinical and biochemical associations with serum cystatin C and iGFR levels. The diagnostic accuracy of cystatin C and commonly used creatinine-based methods of measuring renal function (serum creatinine, the MDRD four-variable and Cockcroft,Gault formulae) for detecting mild and moderate CKD was also compared. Results, In the entire study population the same five variables, age, urinary albumin excretion rates, haemoglobin, history of macrovascular disease and triglyceride levels were independently associated with both cystatin C and iGFR levels. A serum cystatin C level cut-off > 82.1 nmol/l (1.10 mg/l) had the best test characteristics as a screening tool for detecting moderate CKD (< 60 ml/min per 1.73 m2) when compared with creatinine-based methods. At the upper threshold for mild CKD (< 90 ml/min per 1.73 m2), cystatin C also had greater diagnostic accuracy than creatinine, but had similar diagnostic accuracy when compared with creatinine-based formulae for predicting renal function. Conclusions, This study suggests that the clinical and biochemical parameters associated with serum cystatin C levels are closely linked to those associated with GFR and highlights the potential usefulness of screening for moderate or mild CKD in subjects with diabetes by simply measuring serum cystatin C levels. [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] Pharmacokinetics of alizapride in children receiving chemotherapy for solid tumourFUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 3 2001Elisabeth Rey The purpose of the present study was to determine the pharmacokinetics of alizapride to optimize its use in children aged 1 month to 15 years old who were receiving chemotherapy. Seventeen children were given a single 4 mg/kg alizapride infusion prior to the administration of cytostatic drugs. Blood and urine samples were collected within 10 h after onset of the infusion. Kinetic parameters were calculated and showed a decrease in plasma clearance expressed per unit of body weight with age. The current data suggest that dosage expressed per unit of body weight should be higher in children than in adults and higher in infants than in children. [source] Pharmacokinetics and tolerability of modafinil tablets in Chinese subjectsJOURNAL OF CLINICAL PHARMACY & THERAPEUTICS, Issue 4 2008P. Xu PhD Summary Objective:, To investigate the pharmacokinetics and tolerability of modafinil in Chinese subjects. Methods:, Twelve healthy volunteers were given an escalating single dose of modafinil (100, 200 and 400 mg) in a three-period study (study 1). Another 12 volunteers received 100 mg twice daily for 7 days in multiple-dose study (study 2). Blood samples were taken from 0 to 60 h for study 1. And samples for study 2 were collected before administration on three consecutive morning and then from 0 to 60 h after the last dose. Pharmacokinetic parameters were calculated and compared with results from published data. Results:, In study 1, Cmax and area under the concentration,time curve of modafinil and modafinil acid were increased proportionally with dose levels; t1/2 was independent on the dose levels. In study 2, the steady state was reached on day 4, and mean trough plasma concentration of modafinil was 1·36 ± 0·34 ,g/mL. Apparent plasma clearance and apparent volume of distribution were lower in 100 mg twice-daily group than those in 100 mg single group. The adverse events were mild and moderate in study 1 and 2. Conclusions:, In this pharmacokinetic study, modafinil was safe and well tolerated by young healthy Chinese subjects. The major pharmacokinetic parameters of modafinil in Chinese subjects are similar to those reported in Caucasians although the half-life seems to be longer in the former than in the latter. This apparent difference requires investigation. [source] Intra-operative colloid administration increases the clearance of a post-operative fluid loadACTA ANAESTHESIOLOGICA SCANDINAVICA, Issue 3 2009T. BORUP Background: It is unknown whether an intra-operative colloid infusion alters the dynamics of a crystalloid load administered post-operatively. Methods: Ten patients received 12.5 ml/kg of Ringer's lactate over 30 min 1,3 days before and 4 h after laparoscopic cholecystectomy, during which 10 ml/kg of a colloid solution, hydroxyethylstarch (HES 130/0.4), was infused. The total body clearance of the pre- and post-operative test infusions was taken as the ratio between the urinary excretion and the Hb-derived dilution of venous plasma over 150 min. The plasma clearance of the infused fluid was calculated using volume kinetics based on the plasma dilution alone. The pre-operative plasma clearance was compared with the post-operative plasma clearance and patients served as their own control. Results: The urinary excretion averaged 350 ml for the pre-operative infusion and 612 ml post-operatively, which corresponds to 46% and 68% of the pre- and post-operative infusions, respectively. The total body clearance of the crystalloid fluid was 30 ml/min before surgery and 124 ml/min after surgery (P<0.01). The plasma clearance, as obtained from the plasma dilution alone, was 28 and 412 ml/min, respectively. The maximal increase in plasma volume was 410 ml pre-operatively vs. 220 ml post-operatively. Conclusions: Infusion of a colloid solution in combination with a crystalloid during laparoscopic cholecystectomy increased the plasma clearance of a post-operative crystalloid infusion. [source] Synthesis and preliminary biological evaluation of a 99mTc-labeled hypericin derivative as a necrosis avid imaging agentJOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS, Issue 1 2008Humphrey Fonge Abstract Mono-[123I]iodohypericin and mono-[123I]iodohypericin monocarboxylic acid are iodine-123-labeled hypericin derivatives which have shown great promise in preclinical studies as necrosis avid imaging agents in animal models of infarction. In view of the more attractive properties of a 99mTc-labeled hypericin derivative, we have synthesized a conjugate of protohypericin monocarboxylic acid with S -benzoylmercaptoacetyldiglycyl-diaminopentane in an overall yield of 15%. The conjugate was labeled with technetium-99m by exchange labeling at pH 10 in a labeling yield of 95% followed by photocyclization to yield 99mTc-mercaptoacetyldiglycyl-1,5-diaminopentylene hypericincarboxamide (99mTc-13). The negatively charged 99mTc-13 complex was purified by reversed phase high-pressure liquid chromatography and the log,P7.4 was determined to be 2.36. In normal NMRI mice, the complex showed slow hepatobiliary clearance while plasma clearance was rapid. The tracer was evaluated in rats with reperfused hepatic infarction by ex vivo autoradiography, gamma counting and histochemical techniques. Unlike the radioiodinated hypericin derivatives, the new tracer agent did not show preferential uptake in necrotic tissue on autoradiography and gamma counting techniques. Conjugation of hypericin with a 99mTc-chelate, resulting in a change in size, charge and lipophilicity, had a profound effect on the necrosis avidity of the tracer agent. The results show that 99mTc-13 is not suitable for imaging necrosis. Copyright © 2008 John Wiley & Sons, Ltd. [source] Role of P-glycoprotein in pharmacokinetics and drug interactions of digoxin and ,-methyldigoxin in ratsJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 7 2003Sachiyo Funakoshi Abstract Digoxin and ,-methyldigoxin were evaluated pharmacokinetically in terms of P-glycoprotein (P-gp)-mediated drug interactions in rats. Evaluation was made by measuring the effects of a potent P-gp inhibitor (verapamil, cyclosporin A) on in vitro efflux transport of these compounds across the everted small intestine, on in situ absorption from the small intestine, and on in vivo total plasma clearance (CLtotal) as well as biliary and urinary excretions after intravenous administration. Both the intestinal efflux transport and absorption of ,-methyldigoxin were approximately 1.5-fold greater than those of digoxin, probably due to its higher lipophilicity. Addition of verapamil (300 ,M) significantly decreased the intestinal efflux transport and increased the intestinal absorption of digoxin. In contrast, the influence of verapamil on ,-methyldigoxin was small. Intravenous cyclosporin A (30 mg/kg) significantly decreased in vivo CLtotal and biliary excretion of digoxin, but affected little on ,-methyldigoxin clearances. These results suggest that P-gp-mediated drug interactions can easily occur in digoxin, but hardly in ,-methyldigoxin. These findings may give a clue in selecting these digitalis compounds in clinical use, towards escape from P-gp-mediated drug interactions or reduction of interindividual variations. © 2003 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 92:1455,1463, 2003 [source] Contradistinction between doxorubicin and epirubicin: in-vivo metabolism, pharmacokinetics and toxicodynamics after single- and multiple-dosing in ratsJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 7 2001Sandhya Ramanathan-Girish There is compelling in-vitro evidence that the evaluation of doxorubicin or epirubicin pharmacokinetics based solely on plasma concentration may not fully elucidate the differences between the two drugs. Both compounds bind to erythrocytes and their different binding to haemoglobin may influence their disposition in the body. The purpose of the present study was to compare the pharmacokinetics and metabolism of doxorubicin and epirubicin based on the plasma concentration, amount associated with blood cells and simultaneous monitoring of biliary and urinary elimination of unchanged drug and metabolites after single- and multiple-dose injections. The level of sarcoplasmic reticulum Ca2+ ATPase in the heart was also measured as a biomarker of cardiotoxicity. Male Sprague-Dawley rats were treated in a parallel design with doxorubicin or epirubicin on a multiple-dosing basis (4 mg kg,1 per week) or as a single dose injection (20 mg kg,1). Blood, urine and bile samples were collected periodically after each dose in the multiple-dosing regimen and the single dose injection, and at the end of each experiment the hearts were removed. The concentrations of each drug in plasma, blood cells, bile and urine samples were determined, and by simultaneous curve-fitting of plasma and bile data according to compartmental analysis, the pharmacokinetic parameters and constants were estimated. The concentration of drug associated with blood cells was analysed according to non-compartmental analysis. The bile and urine samples provided the in-vivo metabolic data. The level of Ca2+ ATPase in the heart, determined by Western blotting, was used as the toxicodynamic parameter to correlate with the kinetic data. Multiple-dosing regimens reduced the total plasma clearance and increased the area under the plasma concentration-time curve of both drugs. Also, the area under the curve of doxorubicin associated with blood cells increased with the weekly doses, and the related mean residence time (MRT) and apparent volume of distribution (Vdss) were steadily reduced. In contrast to doxorubicin, the MRT and Vdss of epirubicin increased significantly. Metabolic data indicated significant differences in the level of alcohol and aglycones metabolites. Doxorubicinol and doxorubicin aglycones were significantly greater than epirubicinol and epirubicin aglycone, whereas epirubicinol aglycone was greater than doxorubicinol aglycone. The area under the blood cells concentration-time curve correlated linearly with the changes in Ca2+ ATPase net intensity. The results of this study demonstrate the importance of the kinetics of epirubicin and doxorubicin associated with blood cells. Linear correlation between the reduction of net intensity of the biomarker with the area under the curve of doxorubicin associated with blood cells confirms that the differences between the two compounds are related to their interaction with blood cells. This observation together with the observed differences in metabolism may underline a significant role for blood cells in distribution and metabolism of doxorubicin and epirubicin. [source] Comparison of Glomerular Filtration Rate between Greyhounds and Non-Greyhound DogsJOURNAL OF VETERINARY INTERNAL MEDICINE, Issue 3 2006Wm Tod Drost Greyhounds have significantly higher serum creatinine (SCr) concentration than do non-Greyhound dogs that may be attributable to differences in glomerular filtration rate (GFR). By means of plasma clearance of technetium Tc 99m diethylenetriaminepentaacetic acid, GFR was measured in 10 Greyhounds and 10 non-Greyhound dogs with normal findings of physical examination, CBC, serum biochemical analysis, and urinalysis. Dogs were fed the same diet for a minimum of 6 weeks before GFR data collection. Greyhounds had significantly higher mean ± SD GFR (3.0±0.1 vs 2.5±0.2 ml/min/kg; P= .01) and SCr concentration (1.8±0.1 vs 1.5±0.1 mg/dL; P= .03) than did non-Greyhound dogs, but the serum urea nitrogen (SUN) concentration was not significantly different (18±1 vs 18±2 mg/dL; P= .8). Therefore, the higher SCr concentration in Greyhounds is not attributable to decreased GFR, and may be associated with the high muscle mass in the breed. Healthy Greyhounds have higher GFR than do non-Greyhound dogs. [source] Detection and pharmacokinetics of tetrahydrogestrinone in horsesJOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 2 2009M. MACHNIK The anti-doping rules of national and international sport federations ban any use of tetrahydrogestrinone (THG) in human as well as in horse sports. Initiated by the THG doping scandals in human sports a method for the detection of 3-keto-4,9,11-triene steroids in horse blood and urine was developed. The method comprises the isolation of the analytes by a combination of solid phase and liquid,liquid extraction after hydrolysis and solvolysis of the steroid conjugates. The concentrations of THG in blood and urine samples were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS). A THG excretion study on horses was conducted to verify the method capability for the analysis of postadministration urine samples. In addition, blood samples were collected to allow for determination of the pharmacokinetics of THG in horses. Following the administration of a single oral dose of 25 ,g THG per kg bodyweight to 10 horses, samples were collected at appropriate intervals. The plasma levels of THG reached maximal concentrations of 1.5,4.8 ng/mL. Twenty-four hours after the administration plasma levels returned to baseline. In urine, THG was detectable for 36 h. Urinary peak concentrations of total THG ranged from 16 to 206 ng/mL. For the 10 horses tested, the mean plasma clearance of THG was 2250 mL/h/kg and the plasma elimination half-life was 1.9 h. [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] Effect of tepoxalin on renal function in healthy dogs receiving an angiotensin-converting enzyme inhibitorJOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 6 2005M. FUSELLIER The objective of this study was to investigate renal function in clinically normal dogs receiving tepoxalin, a nonsteroidal inflammatory drug, either in association with or without an angiotensin-converting enzyme inhibitor (ACEI). Ten adult female Beagle dogs were used in the three phases of the study. The dogs were administered the drugs once daily for 7 days (experiment 1: placebo/tepoxalin/tepoxalin and benazepril; experiment 2: enalapril/tepoxalin and enalapril) or for 28 days (experiment 3: tepoxalin and benazepril together). Renal function was assessed by measurement of glomerular filtration rate (GFR) by renal scintigraphy [(renal uptake of 99mTc-diethylenetriaminepentacetic acid (DTPA)] and plasma clearance of 99mTc-DTPA. Compared with the placebo group, renal uptake and plasma clearance of 99mTc-DTPA were not significantly modified after a 7-day period of treatment with tepoxalin or enalapril alone, tepoxalin and benazepril or tepoxalin and enalapril together. No significant change was obtained in GFR after a 28-day period of dosing with tepoxalin and benazepril together. Therefore, it was concluded that tepoxalin did not alter renal function in healthy Beagle dogs receiving ACEI. [source] Cystatin C as a marker of renal function immediately after liver transplantationLIVER TRANSPLANTATION, Issue 2 2006Gianni Biancofiore To verify whether cystatin C may be of some use as a renal function marker immediately after orthotopic liver transplantation (OLT), we compared serum cystatin C (SCyst), serum creatinine (Scr), and creatinine clearance (Ccr) levels with the glomerular filtration rate (GFR). On postoperative days 1, 3, 5, and 7, SCyst and Scr was measured in simultaneously drawn blood samples, whereas Ccr was calculated using a complete 24-hour urine collection. The GFR was determined on the same days by means of iohexol plasma clearance (I-GFR). The correlation between 1/SCyst and I-GFR was stronger than that of 1/Scr or Ccr (P< 0.01). In the case of moderate reductions in I-GFR (80-60 mL/minute/1.73 m), Scr remained within the normal range, whereas the increase in Scyst was beyond its upper limit; for I-GFR reductions to lower levels (59-40 mL/minute/1.73 m), Scr increased slightly, whereas Scyst was twice its upper normal limit. When we isolated all of the I-GFR values on days 3, 5, and 7 that were ,30% lower than that recorded on the first postoperative day, SCyst(P< 0.0001) and Scr (P< 0.01) levels were increased, whereas Ccr remained unchanged (P= 0.09). Receiver operating characteristic (ROC) area-under-the-curve analysis showed that the diagnostic accuracy of Scyst was better than that of Scr and Ccr. Scyst levels of 1.4, 1.7, and 2.2 mg/L respectively predicted I-GFR levels of 80, 60, and 40 mL/minute/1.73 m. In conclusion, cystatin C is a reliable marker of renal function during the immediate post-OLT period, especially when the goal is to identify moderate changes in GFR. Liver Transpl 12:285,291, 2006. © 2006 AASLD. [source] Change of glomerular filtration rate in healthy adults with agingNEPHROLOGY, Issue 5 2009XUEFENG SUN SUMMARY Aim: In order to determine the relationship between glomerular filtration rate (GFR) and age, the associated factors, and the accurate method of GFR in healthy adults, we conducted a cross-sectional study in community-dwelling adults in Beijing. Methods: Renal function of 201 clinically healthy subjects was determined using technetium-99 m-labelled diethylene triamine pentacetic acid (99mTc-DTPA). Estimated GFR was calculated with the Cockcroft,Gault (CG) equation, abbreviated Modification of Diet in Renal Disease (MDRD) equation, and plasma clearance of creatinine (Ccr). Serum cystatin C, biomarkers of inflammatory and endothelial cells were analyzed as well. Protein intake, carotid artery intima-media thickness and plaque formation were assayed as well. Results: Glomerular filtration rate was negatively associated with age and the correlation coefficient for 99mTc-GFR, CG-GFR, MDRD-GFR, Ccr were ,0.643, ,0.736, ,0.55 and ,0.619, respectively (P < 0.001), while the correlation coefficient between cystatin C and age was 0.681 (P < 0.001). Estimated GFR were associated with measured GFR, and the correlation coefficient for Ccr, CG-GFR and MDRD-GFR were 0.813, 0.582 and 0.418, respectively (P < 0.001). The area under the receiver,operator curve of Ccr was larger, CG was smaller while MDRD was the smallest, and the difference was significant (P < 0.001). So a predicted equation was presented by cystatin C and C-reactive protein for the elderly. Conclusion: In the clinically healthy adults, GFR declined with age. MDRD and CG equation are not suitable to estimate GFR in healthy adults. The predicted equation established by cystatin C and C-reactive protein may be more accurate. [source] Matrix effects during analysis of plasma samples by electrospray and atmospheric pressure chemical ionization mass spectrometry: practical approaches to their eliminationRAPID COMMUNICATIONS IN MASS SPECTROMETRY, Issue 17 2003Joachim Schuhmacher Some cases of occurrence of matrix effects (mostly ion suppression) in protein-precipitated plasma samples, and their influence on the validity of plasma concentrations and pharmacokinetic parameters, are discussed. The comparison of matrix effects using either electrospray (TurboIonspray, TISP) or atmospheric pressure chemical ionization (APCI) indicated that APCI is less prone to matrix effects. Nevertheless, TISP is usually the first choice of ionization technique since unknown thermally labile metabolites might be present in the plasma samples causing erroneous results. A high impact of ion suppression on the plasma concentrations after intravenous (i.v.) administration was found, depending on the drug formulation (vehicle). Since ion suppression caused significantly lower plasma concentrations (by a factor of up to 5.5) after i.v. dosing, the area under the curve (AUC) was underestimated and the plasma clearance was consequently erroneously high, with an impact on drug candidate selection. By simple stepwise dilution (e.g. 10-fold and 50-fold) of the supernatant of protein-precipitated plasma samples, including all calibration and quality control samples, the matrix effects were recognized and eliminated. Copyright © 2003 John Wiley & Sons, Ltd. [source] Development of predictive quantitative retention,activity relationship models of alkaloids by mixed micellar liquid chromatographyBIOMEDICAL CHROMATOGRAPHY, Issue 2 2010Yu Chen Abstract The mixed micellar liquid chromatography is a mode that uses mixed micellar system of Brij35/SDS (85 : 15) as a mobile phase under adequate experimental conditions, can simulate the resting membrane potential and the conformation of the long hydrophilic polyoxyethylene chains remains unchanged. In this article, the applications of biopartitioning micellar chromatography, using mixed micellar system to describe and estimate bioactivities of alkaloids, has been focused. The BMCBrij35/SDS -QRAR models of half-life time, volume of distribution, plasma clearance and area under concentration,time curve were obtained using Brij35-SDS retention data. The aim is to take a look at the capability of the mixed micellar liquid chromatography model to describe and/or estimate the bioactivity of alkaloids. Copyright © 2009 John Wiley & Sons, Ltd. [source] Preclinical pharmacokinetics and metabolism of 6-(4-(2,5-difluorophenyl)oxazol-5-yl)-3-isopropyl-[1,2,4]-triazolo[4,3- a]pyridine, a novel and selective p38, inhibitor: identification of an active metabolite in preclinical species and human liver microsomesBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 8 2006Amit S. Kalgutkar Abstract The disposition of 6-(4-(2,5-difluorophenyl)oxazol-5-yl)-3-isopropyl-[1,2,4]-triazolo[4,3- a]pyridine (1), a potent and selective inhibitor of mitogen activated protein (MAP) kinase p38,, was characterized in several animal species in support of its selection for preclinical safety studies and potential clinical development. 1 demonstrated generally favorable pharmacokinetic properties in all species examined. Following intravenous (i.v.) administration, 1 exhibited low volumes of distribution at steady state (Vdss) ranging from 0.4,1.3 l/kg (2.4,26 l/m2) in the rat, dog and monkey. Systemic plasma clearance was low in cynomolgus monkeys (6.00 ml/min/kg, 72.0 ml/min/m2) and Sprague-Dawley rats (7.65±1.08 ml/min/kg, 45.9±6.48 ml/min/m2 in male rats and 3.15±0.27 ml/min/kg, 18.9±1.62 ml/min/m2 in female rats) and moderate in beagle dogs (12.3±5.1 ml/min/kg, 246±102 ml/min/m2) resulting in plasma half-lives ranging from 1 to 5 h in preclinical species. Moderate to high bioavailability of 1 was observed in rats (30,65%), dogs (87%) and monkeys (40%) after oral (p.o.) dosing consistent with the in vitro absorption profile of 1 in the Caco-2 permeability assay. In rats, the oral pharmacokinetics were dose dependent over the dose range studied (5, 50 and 100 mg/kg). The principal route of clearance of 1 in rat, dog, monkey and human liver microsomes and in vivo in preclinical species involved oxidative metabolism mediated by cytochrome P450 enzymes. The major metabolic fate of 1 in preclinical species and humans involved hydroxylation on the isopropyl group to yield the tertiary alcohol metabolite 2. In human liver microsomes, this transformation was catalysed by CYP3A4 as judged from reaction phenotyping analysis using isozyme-specific inhibitors and recombinant CYP enzymes. Metabolite 2 was also shown to possess inhibitory potency against p38, in a variety of in vitro assays. 1 as well as the active metabolite 2 were moderately to highly bound to plasma proteins (fu,0.1,0.33) in rat, mouse, dog, monkey and human. 1 as well as the active metabolite 2 did not exhibit competitive inhibition of the five major cytochrome P450 enzymes namely CYP1A2, 2C9, 2C19, 2D6 and 3A4 (IC50>50 µM). Overall, these results indicate that the absorption, distribution, metabolism and excretion (ADME) profile of 1 is relatively consistent across preclinical species and predict potentially favorable pharmacokinetic properties in humans, supporting its selection for toxicity/safety assessment studies and possible investigations in humans as an anti-inflammatory agent. Copyright © 2006 John Wiley & Sons, Ltd. [source] Pharmacokinetics and tissue distribution of intravenous pefloxacin for antibiotic prophylaxis in biliary surgeryBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 7 2002A.R. Gascón Abstract The plasma levels and tissue penetration of pefloxacin were studied after prophylactic administration to patients undergoing elective biliary surgery. Pefloxacin was administered as a single dose of 800 mg given intravenously as an infusion 1 h before surgery. Over a period of two years, cultures of bile and stone were performed after cholecystectomy in order to find the main pathogens present in the geographical area of the hospital of Txagorritxu (Vitoria, Spain), as well as to test the antimicrobial susceptibility of these bacteria to pefloxacin. Thirty seven per cent of the bile and stone cultures were positive, and 75 different species were isolated. E. coli was the predominant microorganism (25%). Other frequent microorganisms were E. faecium (9.3%), S. epidermidis (6.6%) and Cl. perfringens (6.6%). Most species isolated were susceptible to pefloxacin, with MIC90 values of 0.125 ,g/ml for E. coli, 0.5 ,g/ml for S. epidermidis and 1 ,g/ml for Cl. perfringens. E. faecium was resistant, with a MIC90 value of 8 ,g/ml but a MIC50 of 4 ,g/ml (intermediate). After pefloxacin infusion, adequate drug plasma levels (>MIC90) for the most frequent pathogens were found throughout the procedure. Elimination half-life was estimated as 22.03±6.91 h; the area under the concentration,time curve from zero to infinite had a value of 275.07±130.02 mg h/l and the values for volume of distribution at steady-state and plasma clearance were 96.48±28.65 L and 3.60±1.83 l/h, respectively. Bile pefloxacin concentrations generally exceeded the minimum inhibitory concentrations for most relevant pathogens. Drug levels in gallbladder and subcutaneous tissues were also above the MIC90 for extended periods. Patients were observed daily throughout their hospital stay. This included examination of the surgical wound and recording of body temperature. No cases of anaerobic infection were noted in the study patients. Other constants such as hospitalization stay and time of recuperation were normal for this type of surgery. According to these results, pefloxacin presents many features that make it suitable for use as a therapeutic prophylactic agent, such as its broad spectrum of antimicrobial activity and favorable pharmacokinetic properties. Copyright © 2002 John Wiley & Sons, Ltd. [source] Pharmacokinetics of controlled-release verapamil in healthy volunteers and patients with hypertension or anginaBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 1 2002Suneel Gupta Abstract Aims: To study the dose-ranging population pharmacokinetics of controlled release verapamil in healthy subjects and patients with angina or hypertension. To characterize the pharmacodynamics of controlled-release verapamil in patients with hypertension. Methods: Dose-ranging studies were conducted in healthy volunteers and patients with hypertension and angina. Subjects received doses of 120, 180, 360, or 540 mg racemic verapamil as an osmotic controlled-release formulation. A population pharmacokinetic model involving zero-order release of verapamil into the gastrointestinal tract with first-order absorption and elimination was used to describe the steady-state plasma concentration profile for R - and S -verapamil. A population sigmoid Emax pharmacodynamic model was used to describe the effect of R - and S -verapamil on mean arterial blood pressure. Results:S -verapamil had an approximate 4-fold greater apparent clearance than R -verapamil in both healthy volunteers and patients. The apparent plasma clearance of R - and S -verapamil in healthy volunteers decreased over the dose range of 120,540 mg. A similar dose-dependent decrease in apparent plasma clearance was also noted in patients. None of the patient demographic variables examined (age, total body weight, lean body weight, body mass index, and height) explained the variability in verapamil pharmacokinetics. The pharmacodynamic model describing the relationship between verapamil plasma concentration and mean arterial blood pressure indicated that the S -verapamil had a 3.6-fold lower estimated EC50 compared to R -verapamil. Conclusions: The results from this dose-ranging pharmacokinetic investigation in healthy volunteers and patients are consistent with previous reports in healthy subjects. S -verapamil is cleared more rapidly than R -verapamil and the estimated EC50 for S -verapamil was 3.6-fold lower than for R -verapamil. Estimated EC50 values for R - and S -verapamil decreased with increasing age and decreasing weight. Copyright © 2002 John Wiley & Sons, Ltd. [source] Pharmacokinetics of E-6087, a new anti-inflammatory agent, in rats and dogsBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 6 2001Raquel F. Reinoso Abstract The pharmacokinetics of E-6087, a newly developed cyclooxygenase-2 inhibitor, was studied in rats and dogs after single oral and intravenous doses. In both animal species, E-6087 was characterized by a long elimination half-life (20,35 h), a low plasma clearance (0.10,0.22 l h,1 kg,1) and a relatively large volume of distribution (2,6 l kg,1). Oral bioavailability was lower in dogs than in rats whereas a faster elimination was found in rats. Multiple peaks were present regardless of administration route and animal species, suggesting the existence of enterohepatic circulation. Gender effect on the pharmacokinetics of E-6087 was only found in rats, with greater exposure and longer elimination in females than in males. Food intake reduced the bioavailability (,22%) with no apparent changes in the absorption rate. After oral dosing of 1, 5 and 25 mg kg,1 to rats, linearity was lost at the highest dose due to the low aqueous solubility of E-6087. Drug absorption was improved by micronization. E-6087 and E-6132, (a pharmacologically active metabolite), showed different pharmacokinetics. The higher percentage of E-6087 at early times suggests that E-6087 is the main compound responsible for in vivo activity, although E-6132 would contribute to the activity at later times. Copyright © 2001 John Wiley & Sons, Ltd. [source] Age-related differences in the pharmacokinetics of stavudine in 272 children from birth to 16 years: a population analysisBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 1 2007V. Jullien Aims To develop a population pharmacokinetic model for stavudine in children and to investigate the consistency of the currently recommended dose based on adult target concentrations. Methods The pharmacokinetics of stavudine were investigated using a population approach. Individual estimates of CL/F were used to calculate the stavudine dose required to achieve the area under the concentration-time curve reported in adults given recommended doses. Results Stavudine pharmacokinetics were well described by a one-compartment model with zero-order absorption. Typical population estimates (% interindividual variability) of the apparent distribution volume (V/F) and plasma clearance (CL/F) were 40.9 l (32%) and 16.5 l h,1 (38%), respectively. Stavudine V/F and CL/F were similarly related to age. Mean calculated doses (0.61 mg kg,1 for children less than 2 weeks, 1.23 mg kg,1 for children more than 2 weeks with bodyweight less than 30 kg, and 31.5 mg for children with a bodyweight between 30 and 60 kg) were in agreement with the current paediatric doses (0.5 mg kg,1, 1 mg kg,1, and 30 mg, respectively). Conclusions Our findings support the current recommended paediatric dosage regimens for stavudine, as they result in the same exposure to the drug as in adults. [source] EFFECTS OF MORPHINE ON METHOTREXATE DISPOSITION IN MICECLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 4 2004Yuai Li SUMMARY 1.,Morphine has been shown to slow the renal excretion of other drugs. The present study in mice evaluated the effects of morphine on the disposition of methotrexate (MTX), an antimetabolite eliminated by the kidneys. 2.,Mice were injected with morphine (20 mg/kg) or saline s.c. After 30 min, 20,80 mg/kg MTX was injected i.v. Blood and urine samples were assayed for MTX by HPLC. 3.,Morphine reduced plasma clearance (CL) of MTX from 0.147 ± 0.015 to 0.061 ± 0.009 mL/min per g bodyweight (P < 0.01). The area under the plasma concentration,time curve (AUC0,,) was raised by morphine from 151 ± 18 to 369 ± 36 µg·mL per min (P < 0.01). Without morphine administration, 22,27% of an MTX dose was excreted into the urine in 30 min. The corresponding fractions excreted into the urine after morphine were reduced to 15,18% (P < 0.01). 4.,Plasma levels of MTX administered intravenously to mice are elevated by the concomitant administration of morphine, which reduces renal elimination of MTX. [source] Estimating GFR in children with 99mTc-DTPA renography: a comparison with single-sample 51Cr-EDTA clearanceCLINICAL PHYSIOLOGY AND FUNCTIONAL IMAGING, Issue 3 2010Henrik Gutte Summary Glomerular filtration rate (GFR) measurement by 51Cr-ethylenediaminetetraacetic acid (EDTA) and blood sampling in children is usually cumbersome for the patient, parents and laboratory technicians. We have previously developed a method accurately estimating GFR in adults. The aim of the present study was to evaluate the accuracy of this non-invasive method in children. We calculated GFR from 99mTc-diethylene triamine pentaacetic acid (DTPA) renography and compared with 51Cr-EDTA plasma clearance of 29 children between the age of 1 month and 12 years (mean 4·7 years). The correlation between 99mTc-DTPA renography and 51Cr-EDTA plasma clearance was for all children R = 0·96 (n = 29, P<0·0001), for children above 2 years of age R = 0·96 (n = 18, P<0·0001) and for children <2 years R = 0·84 (n = 11, P<0·001). We conclude that assessment of GFR from 99mTc-DTPA renography is reliable and comparable to GFR calculated from 51Cr-EDTA plasma clearance. Because our method is non-invasive and only takes 21 min, it may be preferable in many cases where an assessment of renal function is needed in children especially when renography is performed anyhow. [source] Clinical Pharmacokinetics of the PDT Photosensitizers Porfimer Sodium (Photofrin), 2-[1-Hexyloxyethyl]-2-Devinyl Pyropheophorbide-a (Photochlor) and 5-ALA-Induced Protoporphyrin IXLASERS IN SURGERY AND MEDICINE, Issue 5 2006David A. Bellnier PhD Abstract Background and Objectives Photodynamic therapy (PDT) uses a photosensitizer activated by light, in an oxygen-rich environment, to destroy malignant tumors. Clinical trials of PDT at Roswell Park Cancer Institute (RPCI) use the photosensitizers Photofrin, Photochlor, and 5-ALA-induced protoporphyrin IX (PpIX). In some studies the concentrations of photosensitizer in blood, and occasionally in tumor tissue, were obtained. Pharmacokinetic (PK) data from these individual studies were pooled and analyzed. This is the first published review to compare head-to-head the PK of Photofrin and Photochlor. Study Design/Materials and Methods Blood and tissue specimens were obtained from patients undergoing PDT at RPCI. Concentrations of Photofrin, Photochlor, and PpIX were measured using fluorescence analysis. A non-linear mixed effects modeling approach was used to analyze the PK data for Photochlor (up to 4 days post-infusion; two-compartment model) and a simpler multipatient-data-pooling approach was used to model PK data for both Photofrin and Photochlor (at least 150 days post-infusion; three-compartment models). Physiological parameters were standardized to correspond to a standard (70 kg; 1.818 m2 surface area) man to facilitate comparisons between Photofrin and Photochlor. Results Serum concentration-time profiles obtained for Photofrin and Photochlor showed long circulating half-lives, where both sensitizers could be found more than 3 months after intravenous infusion; however, estimated plasma clearances (standard man) were markedly smaller for Photofrin (25.8 ml/hour) than for Photochlor (84.2 ml/hour). Volumes of distribution of the central compartment (standard man) for both Photofrin and Photochlor were about the size (3.14 L, 4.29 L, respectively) of plasma volume, implying that both photosensitizers are almost 100% bound to serum components. Circulating levels of PpIX were generally quite low, falling below the level of instrument sensitivity within a few days after topical application of 5-ALA. Conclusion We have modeled the PK of Photochlor and Photofrin. PK parameter estimates may, in part, explain the relatively long skin photosensitivity attributed to Photofrin but not Photochlor. Due to the potential impact and limited experimental PK data in the PDT field further clinical studies of photosensitizer kinetics in tumor and normal tissues are warranted. Lasers Surg. Med. © 2006 Wiley-Liss, Inc. [source] Matching Efficacy of Online Hemodiafiltration in Simple Hemodialysis ModeARTIFICIAL ORGANS, Issue 12 2008Detlef H. Krieter Abstract PUREMA H (referred to as PES) is an innovative dialysis membrane for enhanced low-molecular-weight (LMW) protein removal. The purpose of the study was to prove whether its efficacy in hemodialysis (HD) matches that of online hemodiafiltration (HDF) with conventional high-flux membranes. In a prospective, randomized, cross-over study on eight maintenance dialysis patients, treatment efficacy of HD with PES was compared with online postdilution HDF with the two synthetic high-flux membranes polysulfone (referred to as PSU) and Polyamix (referred to as POX). Apart from the infusion of replacement fluid, which was set at 20% of the blood flow rate of 300 mL/min, operating conditions in HD and HDF were kept identical. Small solute and LMW protein plasma clearances as well as the reduction ratio (RR) of cystatin C and retinol-binding protein were not different between the therapies. HDF with POX resulted in a significantly lower myoglobin RR as compared with HD with PES, and HDF with PSU. A 4% higher beta2 -microglobulin RR was determined in HDF with PSU (73 ± 5%) as compared with PES in HD (69 ± 5%). The albumin loss was below 1 g for all treatments. Despite the fact that simple HD did not fully exploit the characteristics of PES, it achieved essentially similar LMW protein removal and albumin loss as compared with online postdilution HDF with the conventional synthetic high-flux membranes PSU and POX. Therefore, HD with PES may have beneficial effects on the outcome of maintenance dialysis patients similar to high-efficiency HDF. [source] Disposition of acamprosate in the rat: Influence of probenecidBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 7 2002Teodoro Zornoza Abstract The purpose of the present study was to investigate the disposition of acamprosate (calcium bis acetyl-homotaurine) in the rat. Initially, we studied the linearity of acamprosate disposition and the fraction of acamprosate excreted unchanged in the urine of the animals. Rats received 9.3, 36.6 or 73.3 mg/kg of the drug as an intravenous bolus. The statistical analysis of the pharmacokinetic parameters did not reveal any significant difference, indicating that acamprosate disposition was linear within the range of the doses assayed. On average, 95% of the administered dose was excreted unchanged in the urine of the animals in the 0,6 h post-administration period indicating that renal excretion is the main elimination route for this drug. Acamprosate was also administered by the intravenous route at three different constant infusion rates (2.65, 132.5 and 530 ,g/min) in order to quantify total (Clt) and renal (Clr) plasma clearances at steady-state conditions. The mean Clr values were, respectively, 4.60±0.42, 4.28±0.52 and 4.08±0.67 ml/min, practically equivalent to the Clt values (4.78±0.38, 4.51±0.36 and 4.21±0.56 ml/min), confirming that the drug is mainly eliminated via renal excretion. Moreover, Clr values were clearly higher than the glomerular filtration rate (2.61±0.26 ml/min), suggesting the existence of a highly efficient tubular secretion mechanism in the renal excretion of the drug. To confirm this hypothesis, two groups of rats were intravenously treated with probenecid (33.3 or 66.6 mg/kg) prior to acamprosate administration (9.3 mg/kg). Probenecid provoked a statistically significant dose-dependent reduction in the total clearance of acamprosate (from 5.8±0.7 ml/min in the control group to 2.6±0.1 ml/min in the animals treated with 66 mg/kg of probenecid) demonstrating the existence of a tubular secretion process on the renal excretion of acamprosate in the rat. Copyright © 2002 John Wiley & Sons, Ltd. 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