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Plasma Protein Binding (plasma + protein_binding)
Selected AbstractsStereoselective halofantrine and desbutylhalofantrine disposition in the rat: cardiac and plasma concentrations and plasma protein bindingBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 1 2002Dion R. Brocks Abstract Halofantrine (HF) is a chiral antimalarial drug known to cause cardiac arrhythmias in susceptible patients. In this study, the cardiac uptake and plasma protein binding of HF and desbutylhalofantrine (DHF) enantiomers were examined in the rat. Rats were given 2 mg/kg of either HF HCl or DHF HCl intravenously, then sacrificed at various times after dosing. Specimens were assayed using stereospecific methods. Uptake of HF and DHF enantiomers into heart was rapid. Substantial concentrations of both HF and DHF enantiomers were observed in rat heart, with stereoselectivity being noted for both in plasma and heart. Stereoselectivity was more pronounced for HF (AUC (+):(,) ratio= 1.58) than DHF (AUC (+):(,) ratio =1.16) in heart tissue. Heart:plasma AUC ratios of 6.8,8.0, and 9.3,21, were observed for HF and DHF enantiomers, respectively, indicating that DHF has greater cardiac uptake than HF itself. Plasma protein binding was extensive for both HF and DHF (>99.95%), and was stereoselective for DHF, with a 38% higher unbound fraction for (,)-DHF than antipode. In contrast, binding of HF enantiomers was nonstereoselective. The lower degree of stereoselectivity for DHF in heart tissues was attributable to its greater stereoselectivity in plasma protein binding. Copyright © 2002 John Wiley & Sons, Ltd. [source] Pharmacodynamic Analysis of the Interaction between Tiagabine and Midazolam with an Allosteric Model That Incorporates Signal TransductionEPILEPSIA, Issue 3 2003Daniël M. Jonker Summary: ,Purpose: The objective of this study was to characterize quantitatively the pharmacodynamic interaction between midazolam (MDL), an allosteric modulator of the ,-aminobutyric acid subtype A (GABAA) receptor, and tiagabine (TGB), an inhibitor of synaptic GABA uptake. Methods: The in vivo concentration,response relation of TGB was determined through pharmacokinetic/pharmacodynamic (PK/PD) modeling. Rats received a single intravenous dose of 10 mg/kg TGB in the absence and the presence of a steady-state plasma concentration of MDL. The EEG response in the 11.5- to 30-Hz frequency band was used as the pharmacodynamic end point. Results: Infusion of MDL resulted in a mean steady-state plasma concentration of 66 ± 3 ng/ml. A significant pharmacokinetic interaction with TGB was observed. MDL inhibited TGB clearance by 20 ± 7 ml/min/kg from the original value of 89 ± 6 ml/min/kg. However, no changes in plasma protein binding of both drugs were observed. The concentration,EEG relation of TGB was described by the sigmoid- Emax model. The pharmacodynamic parameter estimates of TGB were: Emax = 327 ± 10 ,V, EC50 = 392 ± 20 ng/ml, and nH = 3.1 ± 0.3. These values were not significantly different in the presence of MDL. Factors that may explain the lack of synergism were identified by a mechanism-based interaction model that separates the receptor activation from the signal-transduction process. High efficiency of signal transduction and the presence of a baseline response were shown to diminish the degree of synergism. Conclusions: We conclude that the in vivo pharmacodynamic interaction between MDL and TGB is additive rather than synergistic. This strongly suggests that allosteric modulation of the antiseizure activity of a GAT-1 inhibitor by a benzodiazepine does not offer a therapeutic advantage. [source] No pharmacokinetic interaction between paliperidone extended-release tablets and trimethoprim in healthy subjects,HUMAN PSYCHOPHARMACOLOGY: CLINICAL AND EXPERIMENTAL, Issue 7 2009An Thyssen Abstract Objective The effect of trimethoprim, a potent organic cation transport inhibitor, on the pharmacokinetics (PK) of paliperidone extended-release tablets (paliperidone ER), an organic cation mainly eliminated via renal excretion, was assessed. Methods Open-label, two-period, randomized, crossover study in 30 healthy males. Single dose of paliperidone ER 6,mg was administered either alone on day 1 or day 5 during an 8-day treatment period of trimethoprim 200,mg twice daily. Serial blood and urine samples were collected for PK and plasma protein binding of paliperidone and its enantiomers. The 90% confidence interval (CI) of ratios with/without trimethoprim for PK parameters of paliperidone and its enantiomers calculated. Results Creatinine clearance decreased from 119 to 102,mL,min,1 with trimethoprim. Addition of trimethoprim increased unbound fraction of paliperidone by 16%, renal clearance by 13%, AUC, by 9%, and t½ by 19%. The 90% CIs for ratios with/without trimethoprim were within the 80,125% range for Cmax, AUClast, and renal clearance. For AUC,, 90% CI was 79.37,101.51, marginally below the lower bound of the acceptance range. Paliperidone did not affect steady-state plasma concentrations of trimethoprim. Conclusions No clinically important drug interactions are expected when paliperidone ER is administered with organic cation transport inhibitors. Copyright © 2009 John Wiley & Sons, Ltd. [source] Ionization-specific prediction of blood,brain permeabilityJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 1 2009Kiril Lanevskij Abstract This study presents a mechanistic QSAR analysis of passive blood,brain barrier permeability of drugs and drug-like compounds in rats and mice. The experimental data represented in vivo log,PS (permeability-surface area product) from in situ perfusion, brain uptake index, and intravenous administration studies. A data set of 280 log,PS values was compiled. A subset of 178 compounds was assumed to be driven by passive transport that is free of plasma protein binding and carrier-mediated effects. This subset was described in terms of nonlinear lipophilicity and ionization dependences, that account for multiple kinetic and thermodynamic effects: (i) drug's kinetic diffusion, (ii) ion-specific partitioning between plasma and brain capillary endothelial cell membranes, and (iii) hydrophobic entrapment in phospholipid bilayer. The obtained QSAR model provides both good statistical significance (RMSE,<,0.5) and simple physicochemical interpretations (log,P and pKa), thus providing a clear route towards property-based design of new CNS drugs. © 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:122,134, 2009 [source] Prediction of pharmacokinetics prior to in vivo studies.JOURNAL OF PHARMACEUTICAL SCIENCES, Issue 1 2002Abstract In drug discovery and nonclinical development the volume of distribution at steady state (Vss) of each novel drug candidate is commonly determined under in vivo conditions. Therefore, it is of interest to predict Vss without conducting in vivo studies. The traditional description of Vss corresponds to the sum of the products of each tissue:plasma partition coefficient (Pt:p) and the respective tissue volume in addition to the plasma volume. Because data on volumes of tissues and plasma are available in the literature for mammals, the other input parameters needed to estimate Vss are the Pt:p's, which can potentially be predicted with established tissue composition-based equations. In vitro data on drug lipophilicity and plasma protein binding are the input parameters used in these equations. Such a mechanism-based approach would be particularly useful to provide first-cut estimates of Vss prior to any in vivo studies and to explore potential unexpected deviations between sets of predicted and in vivoVss data, when the in vivo data become available during the drug development process. The objective of the present study was to use tissue composition-based equations to predict rat and human Vss prior to in vivo studies for 123 structurally unrelated compounds (acids, bases, and neutrals). The predicted data were compared with in vivo data obtained from the literature or at Roche. Overall, the average ratio of predicted-to-experimental rat and human Vss values was 1.06 (SD,=,0.817, r,=,0.78, n,=,147). In fact, 80% of all predicted values were within a factor of two of the corresponding experimental values. The drugs can therefore be separated into two groups. The first group contains 98 drugs for which the predicted Vss were within a factor of two of those experimentally determined (average ratio of 1.01, SD,=,0.39, r,=,0.93, n,=,118), and the second group includes 25 other drugs for which the predicted and experimental Vss differ by a factor larger than two (average ratio of 1.32, SD,=,1.74, r,=,0.42, n,=,29). Thus, additional relevant distribution processes were neglected in predicting Vss of drugs of the second group. This was true especially in the case of some cationic-amphiphilic bases. The present study is the first attempt to develop and validate a mechanistic distribution model for predicting rat and human Vss of drugs prior to in vivo studies. © 2002 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 91:129,156, 2002 [source] Validation of subcutaneous microdialysis sampling for pharmacokinetic studies of flurbiprofen in the ratJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 11 2001François-xavier Mathy Abstract The objective of this study was to validate subcutaneous (sc) microdialysis sampling to study flurbiprofen pharmacokinetics and plasma protein binding in the awake freely moving rat. A linear microdialysis probe was manufactured using a Hemophane® hollow fiber which was tested in vitro and in vivo for the recovery of flurbiprofen and naproxen used as retrodialysis marker. Flurbiprofen was administered intraperitoneally and intravenously at a dose of 20 mg/kg in rats. In both cases, conventional blood sampling and sc microdialysis sampling were simultaneously performed. The microdialysates were analyzed on-line by high-pressure liquid chromatography. Naproxen, which was shown to have a similar in vivo loss by retrodialysis as flurbiprofen (71.5,±,0.9% and 71.0,±,0.8% respectively, n,=,3), was used to continuously monitor probe recovery. Concentration-dependent protein binding of flurbiprofen was demonstrated in vivo based on experiments with a simultaneous sc microdialysis and blood sampling. Values of unbound fraction were similar to those reported previously by intravenous microdialysis sampling, demonstrating that the sc unbound concentrations are very similar to those in the central compartment. There was no significant difference among pharmacokinetic parameters (AUC, CL, t1/2z, Vd) for total or unbound flurbiprofen determined after intraperitoneal and intravenous administration. Subcutaneous microdialysis is a simple yet powerful tool to study the pharmacokinetics and the in vivo plasma protein binding of flurbiprofen in the awake unrestrained rat. © 2001 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 90:1897,1906, 2001 [source] Pharmacokinetics of gamithromycin in cattle with comparison of plasma and lung tissue concentrations and plasma antibacterial activityJOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 3 2010R. A. HUANG Huang, R. A., Letendre, L. T., Banav, N., Fischer, J., Somerville, B. Pharmacokinetics of gamithromycin in cattle with comparison of plasma and lung tissue concentrations and plasma antibacterial activity. J. vet. Pharmacol. Therap.33, 227,237. The pharmacokinetics (PK) and dose proportionality of gamithromycin (ZACTRAN®), a novel azalide, after a single intravenous (i.v.) dose of 3 mg/kg or subcutaneous (s.c.) injection at 3, 6 and 9 mg/kg body weight were studied in 13 male castrate and 13 female Angus cattle. Following i.v. administration, the mean area under the curve extrapolated to infinity (AUCinf) was 4.28 ± 0.536 ,g·h/mL, and mean elimination half-life (t1/2) was 44.9 ± 4.67 h, with a large volume of distribution (Vss) of 24.9 ± 2.99 L/kg and a high clearance rate (Clobs) of 712 ± 95.7 mL/h/kg. For cattle treated with s.c. injection of 3, 6 or 9 mg/kg, mean AUCinf values were 4.55 ± 0.690, 9.42 ± 1.11 and 12.2 ± 1.13 ,g·h/mL, respectively, and the mean elimination half-lives (t1/2) were 51.2 ± 6.10, 50.8 ± 3.80 and 58.5 ± 5.50 h. Gamithromycin was well absorbed and fully bioavailable (97.6,112%) after s.c. administration. No statistically significant (, = 0.05) gender differences in the AUCInf or elimination half-life values were observed. Dose proportionality was established based on AUCInf over the range of 0.5 to 1.5 times of the recommended dosage of 6 mg/kg of body weight. Further investigations were conducted to assess plasma PK, lung/plasma concentration ratios and plasma antibacterial activity using 36 cattle. The average maximum gamithromycin concentration measured in whole lung homogenate was 18 500 ng/g at first sampling time of 1 day (,24 h) after treatment. The ratios of lung to plasma concentration were 265, 410, 329 and 247 at 1, 5, 10 and 15 days postdose. The lung AUCinf was 194 times higher than the corresponding plasma AUCinf. The apparent elimination half-life for gamithromycin in lung was 90.4 h (,4 days). Antibacterial activity was observed with plasma collected at 6 h postdose with a corresponding average gamithromycin plasma concentration of 261 ng/mL. In vitro plasma protein binding in bovine plasma was determined to be 26.0 ± 0.60% bound over a range of 0.1,3.0 ,g/mL of gamithromycin. The dose proportionality of AUC, high bioavailability, rapid and extensive distribution to lung tissue and low level of plasma protein binding are beneficial PK parameters for an antimicrobial drug used for the treatment and prevention of bovine respiratory disease. [source] Pharmacokinetics of cefepime administered by i.v. and i.m. routes to ewesJOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 6 2005M. ISMAIL The pharmacokinetics of cefepime were studied following i.v. and i.m. administration of 20 mg/kg in 10 ewes. Following i.v. administration of a single dose, the plasma concentration,time curves of cefepime were best fitted using a two-compartment open model. The elimination half-life (t1/2,) was 1.76 ± 0.07 h, volume of distribution at steady-state [Vd(ss)] was 0.32 ± 0.01 L/kg and total body clearance (ClB) was 2.37 ± 0.05 mL/min·kg. Following i.m. administration, the drug was rapidly absorbed with an absorption half-life (t1/2ab) of 0.49 ± 0.05 h, maximum plasma concentration (Cmax) of 31.9 ± 1.5 ,g/mL was attained at (tmax) 1.1 ± 0.2 h and the drug was eliminated with an elimination half-life (t1/2el) of 2.06 ± 0.11 h. The systemic bioavailability (F) after i.m. administration of cefepime was 86.8 ± 7.5%. The extent of plasma protein binding measured in vitro was 14.8 ± 0.54%. The drug was detected in urine for 36 h postadministration by both routes. [source] Airway Selectivity: An Update of Pharmacokinetic Factors Affecting Local and Systemic Disposition of Inhaled SteroidsBASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 6 2006Staffan Edsbäcker The antiinflammatory properties of these products, combined with the targeting of formulations and optimization of the intrinsic pharmacokinetic features of the newer corticosteroid molecules has resulted in substantially improved airway selectivity. This review sets out to summarize the pharmacokinetic properties of inhaled corticosteroids that are important for the achievement of high levels of airway selectivity, with additional focus on the use of prodrugs/softdrugs relative to those of conventional corticosteroid molecules, mechanisms (such as esterification) by which retention at the target site is achieved while minimizing systemic exposure, and the role of plasma protein binding. [source] Microseparation techniques for the study of the enantioselectivity of drug,plasma protein bindingBIOMEDICAL CHROMATOGRAPHY, Issue 3 2009Laura Escuder-Gilabert Abstract Stereoselectivity in protein binding can have a significant effect on the pharmacokinetic and pharmacodynamic properties of chiral drugs. The investigation of enantioselectivity of drugs in their binding with human plasma proteins and the identification of the molecular mechanisms involved in the stereodiscrimination by the proteins represent a great challenge for clinical pharmacology. In this review, the separation techniques used for enantioselective protein binding experiments are described and compared. An overview of studies on enantiomer,protein interactions, enantiomer,enantiomer interactions as well as chiral drug,drug interactions, including allosteric effects, is presented. The contribution of individual plasma proteins to the overall enantioselective binding and the animal species variability in drug,plasma protein binding stereoselectivity are reviewed. Copyright © 2008 John Wiley & Sons, Ltd. [source] Binding to dipeptidyl peptidase-4 determines the disposition of linagliptin (BI 1356) , investigations in DPP-4 deficient and wildtype ratsBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 8 2009Silke Retlich Abstract Linagliptin (BI 1356) is a novel dipeptidyl peptidase-4 (DPP-4) inhibitor in clinical development for the treatment of type 2 diabetes. It exhibits non-linear pharmacokinetics and shows concentration-dependent plasma protein binding to its target, DPP-4. The aim of this study was to investigate the impact of saturable binding of linagliptin to plasma and tissue DPP-4 by comparing the pharmacokinetics of linagliptin in wildtype and DPP-4 deficient Fischer rats using non-compartmental and model-based data analysis. The non-compartmental analysis revealed a significantly reduced AUC in DPP-4 deficient rats compared with wildtype rats when single intravenous doses ,1,mg/kg were administered, but the exposure was similar in both strains at higher doses. The terminal half-lives were significantly shorter in DPP-4 deficient rats compared with wildtype rats. For doses ,1,mg/kg, DPP-4 deficient rats exhibited linear pharmacokinetics, whereas the pharmacokinetics of wildtype rats was non-linear. In the model-based analysis these differences could be accounted for by assuming concentration-dependent protein binding in the central and one peripheral compartment in wildtype rats. In the model, disposition parameters for unbound linagliptin were assumed to be identical in both rat strains. Simulations with different doses of linagliptin and different concentrations of binding sites further illustrated that the interdependence of linagliptin and DPP-4 in plasma and in the periphery has a major influence on the disposition of linagliptin in wildtype rats. In conclusion, the study showed that the concentration-dependent binding of linagliptin to its target DPP-4 has a major impact on the plasma pharmacokinetics of linagliptin. Copyright © 2009 John Wiley & Sons, Ltd. [source] Faster clearance of omeprazole in mutant Nagase analbuminemic rats: possible roles of increased protein expression of hepatic CYP1A2 and lower plasma protein bindingBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 3 2009Dae Y. Lee Abstract It is well known that there are various changes in the expression of hepatic and intestinal CYPs in mutant Nagase analbuminemic rats (NARs). It has been reported that the protein expression of hepatic CYP1A2 was increased, whereas that of hepatic CYP3A1 was not altered, and it was also found that the protein expression of the intestinal CYP1A subfamily significantly increased in NARs from our other study. In addition, in this study additional information about CYP changes in NARs was obtained; the protein expression of the hepatic CYP2D subfamily was not altered, but that of the intestinal CYP3A subfamily increased in NARs. Because omeprazole is metabolized via hepatic CYP1A1/2, 2D1, 3A1/2 in rats, it could be expected that the pharmacokinetics of omeprazole would be altered in NARs. After intravenous administration of omeprazole to NARs, the Clnr was significantly faster than in the controls (110 versus 46.6 ml/min/kg), and this could be due to an increase in hepatic metabolism caused by a greater hepatic CYP1A2 level in addition to greater free fractions of the drug in NARs. After oral administration of omeprazole to NARs, the AUC was also significantly smaller (80.1% decrease) and F was decreased in NARs. This could be primarily due to increased hepatic and intestinal metabolism caused by greater hepatic CYP1A2 and intestinal CYP1A and 3A levels. In particular, the smaller F could mainly result from greater hepatic and intestinal first-pass effect in NARs than in the controls. Copyright © 2009 John Wiley & Sons, Ltd. [source] Prediction of human oral pharmacokinetics using nonclinical data: examples involving four proprietary compoundsBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 8 2008Aberra Fura Abstract The oral pharmacokinetics (concentration-time profile) of four proprietary compounds in humans were predicted using the Cvss - MRT method. The first step was to demonstrate superposition of intravenous (i.v.) pharmacokinetic profiles of preclinical species following mathematical transformation of their respective concentration-time curves using the corresponding Cvss (where Cvss=dose/Vss; Vss is the volume of distribution at steady state) and mean residence time (MRT) values. The resultant profiles were then back-transformed to estimate human i.v. plasma concentration-time profiles using human Cvss and MRT values. Human Cvss and MRT values were estimated from projected human Vss and CL values. Projection of CL was based on scaled (in vitro) metabolic clearance, simple allometry with and without various correction factors and the unbound fraction corrected intercept method. Vss values were estimated by allometric scaling with and without correction for interspecies differences in plasma protein binding. The predicted human i.v. profiles, in combination with the estimated mean absorption rate constants and bioavailability, were then used to simulate the oral pharmacokinetics in human using one- or multi-compartment kinetic models. Overall, with this approach, key oral pharmacokinetic parameters such as AUC, Cmax, Cmin and oral plasma T½ were projected to be within two-fold of the actual values in humans. Copyright © 2008 John Wiley & Sons, Ltd. [source] Pharmacokinetics and pharmacodynamics of intravenous trasemide in mutant nagase aalbuminemic ratsBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 1 2003Eun J. Kim Abstract The importance of plasma protein binding of intravenous furosemide in circulating blood for its urinary excretion and hence its diuretic effects in mutant Nagase analbuminemic rats (NARs, an animal model for human familial analbuminemia) was reported. Based on the furosemide report, the diuretic effects of another loop diuretic, torasemide, could be expected in NARs if plasma protein binding of torasemide is considerable in the rats. This was proven by this study. After intravenous administration of torasemide, 10 mg/kg, to NARs, the plasma protein binding of torasemide was 23.3% in the rats due to binding to , - and , -globulins (this value, 23.3%, was greater than only 12% for furosemide), and hence the percentages of intravenous dose of torasemide excreted in 8-h urine as unchanged drug was 14.9% in the rat (this value was considerably greater than only 7% for furosemide). After intravenous administration of torasemide to NARs, the AUC (301 versus 2680 µg/min/ml) was significantly smaller [due to significantly faster both Clr (4.81 versus 0.386 ml/min/kg) and Clnr (28.3 versus 3.33 ml/min/kg)], terminal half-life (18.3 versus 73.5 min) and mean residence time (6.97 versus 61.8 min) were significantly shorter (due to faster Cl, 33.2 versus 3.74 ml/min/kg), and amount of 8-h urinary excretion of unchanged torasemide (446 versus 323 µg, due to increase in intrinsic renal excretion) was significantly greater than those in control rats. The 8-h urine output and 8-h urinary excretions of sodium and chloride were comparable between two groups of rats although the 8-h urinary excretion of torasemide was significantly greater in NARs. This could be explained by the following. The amount of urinary excretion of torasemide was significantly greater in NARs than that in control rats only between 0 and 30 min urine collection. In both groups of rats, the urinary excretion rate of torasemide during 0,30 min reached an upper plateau with respect to urine flow rate as well urinary excretion rates of sodium and chloride. Therefore, the diuretic effects (8-h urine output and 8-h urinary excretions of sodium and chloride) were not significantly different between the two groups of rats. Copyright © 2002 John Wiley & Sons, Ltd. [source] Stereoselective halofantrine and desbutylhalofantrine disposition in the rat: cardiac and plasma concentrations and plasma protein bindingBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 1 2002Dion R. Brocks Abstract Halofantrine (HF) is a chiral antimalarial drug known to cause cardiac arrhythmias in susceptible patients. In this study, the cardiac uptake and plasma protein binding of HF and desbutylhalofantrine (DHF) enantiomers were examined in the rat. Rats were given 2 mg/kg of either HF HCl or DHF HCl intravenously, then sacrificed at various times after dosing. Specimens were assayed using stereospecific methods. Uptake of HF and DHF enantiomers into heart was rapid. Substantial concentrations of both HF and DHF enantiomers were observed in rat heart, with stereoselectivity being noted for both in plasma and heart. Stereoselectivity was more pronounced for HF (AUC (+):(,) ratio= 1.58) than DHF (AUC (+):(,) ratio =1.16) in heart tissue. Heart:plasma AUC ratios of 6.8,8.0, and 9.3,21, were observed for HF and DHF enantiomers, respectively, indicating that DHF has greater cardiac uptake than HF itself. Plasma protein binding was extensive for both HF and DHF (>99.95%), and was stereoselective for DHF, with a 38% higher unbound fraction for (,)-DHF than antipode. In contrast, binding of HF enantiomers was nonstereoselective. The lower degree of stereoselectivity for DHF in heart tissues was attributable to its greater stereoselectivity in plasma protein binding. Copyright © 2002 John Wiley & Sons, Ltd. [source] Pharmacokinetics and pharmacodynamics of intravenous bumetanide in mutant nagase analbuminemic rats: importance of globulin binding for the pharmacodynamic effectsBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 4 2001Eun J. Kim Abstract The importance of plasma protein binding of intravenous furosemide in circulating blood for its urinary excretion and hence its diuretic effects in mutant Nagase analbuminemic rats was reported. Based on the furosemide report, the diuretic effects of another loop diuretic, bumetanide, could be expected in analbuminemic rats if plasma protein binding of bumetanide is considerable in the rats. This was proved by this study. After intravenous administration of bumetanide, 10 mg/kg, to analbuminemic rats, the plasma protein binding of bumetanide was 36.8% in the rats mainly due to considerable binding to , - and , -globulins (this value, 36.8%, was considerably greater than only 12% for furosemide), and hence the percentages of intravenous dose of bumetanide excreted in 6 h urine as unchanged drug was 16.0% in the rat (this value was considerably greater than only 7% for furosemide). After intravenous administration of bumetanide to analbuminemic rats, the area under the plasma concentration,time curve from time zero to time infinity (1012 compared with 2472 ,g min/mL) was significantly smaller [due to significantly faster both renal clearance (1.49 compared with 0.275 ml/min/kg) and nonrenal clearance (8.30 compared with 3.71 ml/min/kg)], terminal half-life (9.94 compared with 22.4 min) and mean residence time (4.25 compared with 5.90 min) were significantly shorter (due to faster total body clearance, 9.88 compared with 4.05 ml/min/kg), and amount of 6 h urinary excretion of unchanged bumetanide (559 compared with 261 ,g, due to increase in intrinsic renal excretion) was significantly greater than that in control rats. The 6 h urine output and 6 h urinary excretions of sodium, chloride and potassium were comparable between two groups of rats although the 6 h urinary excretion of bumetanide was significantly greater in analbuminemic rats. This could be explained by the following. The amount of urinary excretion of bumetanide was significantly greater in analbuminemic rats than that in control rats only between 0 and 30 min urine collection. In both groups of rats, the urinary excretion rates of bumetanide during 0,30 min reached a upper plateau with respect to urine flow rate as well urinary excretion rates of sodium, potassium and chloride, therefore, the diuretic effects (6 h urine output and 6 h urinary excretions of sodium, potassium and chloride) were not significantly different between two groups of rats. Copyright © 2001 John Wiley & Sons, Ltd. [source] Stereoselective pharmacokinetics of clausenamide enantiomers and their major metabolites after single intravenous and oral administration to ratsCHIRALITY, Issue 8 2003Chuan Jiang Zhu Abstract The pharmacokinetics of clausenamide (CLA) enantiomers and their metabolites were investigated in Wistar rat. After intravenous and oral administration at a dose of 80 and 160 mg/kg each enantiomer, plasma concentrations of (,)- or (+)-CLA and its major metabolites were simultaneously determined by reverse-phase HPLC with UV detection. Notably, stereoselective differences in pharmacokinetics were found. The mean plasma levels of (+)-CLA were higher at almost all time points than those of (,)-CLA. (+)-CLA also exhibited greater tmax, Cmax, t1/2,, AUC0,12h, and AUC0,, and smaller CL (or CL/F) and Vd (or Vd/F), than its antipode. The (+)/(,) isomer ratios for t1/2,, tmax, AUC0,12 h, and AUC0,,, which ranged from 1.26 to 2.08. The ratio for CL (or CL/F) was about 0.5, and there were significant differences in these values between CLA enantiomers (P < 0.05), implying that the absorption, distribution, and elimination of (,)-CLA were more rapid than those of (+)-CLA. Similar findings for (,)-7-OH-CLA, the major metabolite of (,)-CLA, and (+)-4-OH-CLA, the major metabolite of (+)-CLA, can be also seen in rat plasma. The contributing factors for the differences in stereoselective pharmacokinetics of CLA enantiomers appeared to be involved in their different plasma protein binding, first-pass metabolism and interaction with CYP enzymes, especially with their metabolizing enzyme CYP 3A isoforms. Chirality 15:668,673, 2003. © 2003 Wiley-Liss, Inc. [source] | |||||||||||||