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Peripheral Compartment (peripheral + compartment)
Selected AbstractsBinding 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] Population pharmacokinetic analysis of cilostazol in healthy subjects with genetic polymorphisms of CYP3A5, CYP2C19 and ABCB1BRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 1 2010Hee-Doo Yoo WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT , The interindividual variability of the pharmacokinetic parameters of cilostazol is relatively large. , Cilostazol undergoes extensive hepatic metabolism via the P450 enzymes, primarily CYP3A and, to a lesser extent, CYP2C19. , Indeed, <1% of the administered dose of cilostazol is excreted unchanged in the urine. WHAT THIS STUDY ADDS , A population pharmacokinetic analysis of cilostazol was conducted to evaluate the impact of CYP3A, CYP2C19 and ABCB1 polymorphisms on cilostazol disposition in vivo. , Genetic polymorphisms of CYP3A5 and CYP2C19 explain the substantial interindividual variability in the pharmacokinetics of cilostazol. , ABCB1 genotypes do not to appear to be associated with the disposition of cilostazol. AIMS To investigate the influence of genetic polymorphisms in the CYP3A5, CYP2C19 and ABCB1 genes on the population pharmacokinetics of cilostazol in healthy subjects. METHODS Subjects who participated in four separate cilostazol bioequivalence studies with the same protocols were included in this retrospective analysis. One hundred and four healthy Korean volunteers were orally administered a single 50- or 100-mg dose of cilostazol. We estimated the population pharmacokinetics of cilostazol using a nonlinear mixed effects modelling (nonmem) method and explored the possible influence of genetic polymorphisms in CYP3A (CYP3A5*3), CYP2C19 (CYP2C19*2 and CYP2C19*3) and ABCB1 (C1236T, G2677T/A and C3435T) on the population pharmacokinetics of cilostazol. RESULTS A two-compartment model with a first-order absorption and lag time described the cilostazol serum concentrations well. The apparent oral clearance (CL/F) was estimated to be 12.8 l h,1. The volumes of the central and the peripheral compartment were characterized as 20.5 l and 73.1 l, respectively. Intercompartmental clearance was estimated at 5.6 l h,1. Absorption rate constant was estimated at 0.24 h,1 and lag time was predicted at 0.57 h. The genetic polymorphisms of CYP3A5 had a significant (P < 0.001) influence on the CL/F of cilostazol. When CYP2C19 was evaluated, a significant difference (P < 0.01) was observed among the three genotypes (extensive metabolizers, intermediate metabolizers and poor metabolizers) for the CL/F. In addition, a combination of CYP3A5 and CYP2C19 genotypes was found to be associated with a significant difference (P < 0.005) in the CL/F. When including these genotypes, the interindividual variability of the CL/F was reduced from 34.1% in the base model to 27.3% in the final model. However, no significant differences between the ABCB1 genotypes and cilostazol pharmacokinetic parameters were observed. CONCLUSIONS The results of the present study indicate that CYP3A5 and CYP2C19 polymorphisms explain the substantial interindividual variability that occurs in the metabolism of cilostazol. [source] Pharmacokinetics of ribavirin in patients with hepatitis C virusBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 6 2006Janet R. Wade Aim A population pharmacokinetic analysis was performed using plasma concentration data (n = 7025) from 380 patients to examine the relationship between ribavirin dose and its pharmacokinetics. Methods Ribavirin pharmacokinetics were described by a three-compartment model with sequential zero-order and a first-order absorption processes. Interoccasion variability and food effects were included. Results Lean body weight (range 41,91 kg) was the only covariate with a clinically significant influence on ribavirin pharmacokinetics, affecting clearance (15.3,23.9 l h,1) and the volume of the larger peripheral compartment. Conclusion The model provided a good description of the available data, confirmed by accurate estimates of parameter values and low residual variability (17%). [source] The effects of the cyclosporin A, a P-glycoprotein inhibitor, on the pharmacokinetics of baicalein in the rat: a microdialysis studyBRITISH JOURNAL OF PHARMACOLOGY, Issue 8 2002T H Tsai Baicalein is a bioactive flavonoid isolated from the root of Scutellaria baicalensis Georgi, a medicinal herb that has been used since ancient times to treat bacterial infections. As little is known concerning its pharmacokinetics, this study focussed on its pharmacokinetics as well as the possible roles of the multidrug transporter P-glycoprotein on its distribution and disposition. Three microdialysis probes were simultaneously inserted into the jugular vein, the hippocampus and the bile duct of male Sprague,Dawley rats for sampling in biological fluids following the administration of baicalein (10, 30 and 60 mg kg,1) through the femoral vein. The P-glycoprotein inhibitor cyclosporin A was used to help delineate its roles. The study design consisted of two groups of six rats in parallel: control rats which received baicalein alone and the cyclosporin A treated-group in which the rats were injected cyclosporin A, a P-glycoprotein inhibitor, 10 min prior to baicalein administration. Cyclosporin A treatment resulted in a significant increase in elimination half-life, mean residence time and area under the concentration versus time curve (AUC) of unbound baicalein in the brain. However, AUC in the bile was decreased. The decline of baicalein in the hippocampus, blood and bile suggested that there was rapid exchange and equilibration between the peripheral compartment and the central nervous system. In addition, the results indicated that baicalein was able to penetrate the blood,brain barrier as well as undergoing hepatobiliary excretion. Although no direct transport studies were undertaken and multiple factors may affect BBB penetration and hepatobiliary excretion, strong association of the involvement of P-glycoprotein in these processes is indicated. British Journal of Pharmacology (2002) 137, 1314,1320. doi:10.1038/sj.bjp.0704959 [source] Marginal zone B cell enrichment and strong follicular B cell reduction correlate with a delayed IgG response in a light chain diversity restricted mouse modelEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 10 2004Yacine Abstract Recently developed B6.,,,SEG mice (by crossing ,, and C57BL/6 mice congenic for the wild Mus spretus SEG strain , locus lacking genes coding for ,1 and ,3) have a very reduced light chain diversity. B6.,,,SEG mice produce only ,2 and ,x light chains. Regardless of their Igh haplotype, B6.,,,SEG mice show a restricted B cell distribution by light chain subtype with ,x dominance in all peripheral compartments except peritoneal cavity where ,2 is dominant. This distribution suggests that selection mechanisms act differently in different B cell compartments on ,2 and ,x bearing B cells. Sequence analysis before or following immunization did not reveal unusual mechanisms of diversification. B6.,,,SEG mice still respond to various challenging antigens using new Ab patterns. In particular, regardless of Igha or Ighb haplotypes, the anti-2,4-dinitrophenyl response is characterized by a restricted diversity for both heavy and light chains and a delayed IgG response when compared to B6 and B6.,, mice. We suggest that the delayed IgG response is due to the expansion of marginal zone B cells whereas follicular B cells are strongly reduced. [source] Population pharmacokinetics of mycophenolic acid in children and young people undergoing blood or marrow and solid organ transplantationBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 4 2010Lihua Zeng WHAT IS ALREADY KNOWN ABOUT THIS PROJECT? , Mycophenolate mofetil (MMF) is an immunosuppressant drug used for the treatment and prevention of graft vs. host disease in blood or marrow transplantation and acute graft rejection in solid organ transplantation. , Mycophenolic acid (MPA) pharmacokinetics have not been thoroughly studied in paediatric blood or marrow transplant recipients and guidance for optimal dosing of mycophenolic acid in children is lacking. , Mycophenolic acid exhibits considerable inter- and intra-patient pharmacokinetic variability in adults and paediatric transplant recipients. , The AUC of mycophenolic acid over a 12 h dose interval at steady-state is generally agreed to be the most reliable metric associated with the risk of acute rejection. , Population pharmacokinetic analysis can utilize concentration information from both intensive sampling and sparse sampling to provide pharmacokinetic parameter estimates, estimates of inter- individual and intra-individual variability in these parameters and allows patient characteristics explaining inter-individual variability to be quantified. WHAT THIS STUDY ADDS , This study is one of the first investigations in which a population pharmacokinetic modelling approach was applied to assess the pharmacokinetics of both intravenous and oral MMF in children and young people undergoing blood or marrow and solid organ transplantation. , Bodyweight and concomitant ciclosporin were found to influence MPA pharmacokinetics. , This study evaluated current dosing strategies and found that they may be suboptimal for children weighing less than 10 kg. AIMS To characterize the population pharmacokinetics of mycophenolic acid (MPA) and evaluate dose regimens using a simulation approach and accepted therapeutic drug monitoring targets in children and young people undergoing blood or marrow, kidney and liver transplantation. METHODS MPA concentration,time data were collected using an age specific sampling protocol over 12 h. Some patients provided randomly timed but accurately recorded blood samples. Total and unbound MPA were measured by HPLC. NONMEM was employed to analyze MPA pharmacokinetic data. Simulations (n= 1000) were conducted to assess the suitability of the MPA dose regimens to maintain total MPA AUC(0,12 h) within the range 30 and 60 mg l,1 h associated with optimal outcome. RESULTS A two-compartment pharmacokinetic model with first-order elimination best described MPA concentration,time data. Population mean estimates of MPA clearance, inter-compartmental clearance, volumes of distribution in the central and peripheral compartments, absorption rate constant and bioavailability were 6.42 l h,1, 3.74 l h,1, 7.24 l, 16.8 l, 0.39 h,1 and 0.48, respectively. Inclusion of bodyweight and concomitant ciclosporin reduced the inter-individual variability in CL from 54.3% to 31.6%. Children with a bodyweight of 10 kg receiving standard MPA dose regimens achieve an MPA AUC below the target range suggesting they may be at a greater risk of acute rejection. CONCLUSIONS The population pharmacokinetic model for MPA can be used to explore dosing guidelines for safe and effective immunotherapy in children and young people undergoing transplantation. [source] | ||||||||||