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Use of mechanistic modeling to assess interindividual variability and interspecies differences in active uptake in human and rat hepatocytes

Drug metabolism and disposition, 2012-09, Vol.40 (9), p.1744-1756 [Peer Reviewed Journal]

Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics 2012 ;ISSN: 0090-9556 ;EISSN: 1521-009X ;DOI: 10.1124/dmd.112.046193 ;PMID: 22665271

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Title:
Use of mechanistic modeling to assess interindividual variability and interspecies differences in active uptake in human and rat hepatocytes
Author: Ménochet, Karelle ; Kenworthy, Kathryn E ; Houston, J Brian ; Galetin, Aleksandra
Subjects: Angiotensin II Type 1 Receptor Blockers - metabolism ; Angiotensin II Type 1 Receptor Blockers - pharmacology ; Animals ; Antihypertensive Agents - metabolism ; Antihypertensive Agents - pharmacology ; Benzimidazoles - metabolism ; Benzimidazoles - pharmacology ; Benzoates - metabolism ; Benzoates - pharmacology ; Biological Transport ; Carbamates - metabolism ; Carbamates - pharmacology ; Dose-Response Relationship, Drug ; Drug Interactions ; Fluorobenzenes - metabolism ; Fluorobenzenes - pharmacology ; Hepatocytes - drug effects ; Hepatocytes - metabolism ; Humans ; Hydroxymethylglutaryl-CoA Reductase Inhibitors - metabolism ; Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology ; Hypoglycemic Agents - metabolism ; Hypoglycemic Agents - pharmacology ; Kinetics ; Models, Biological ; Organic Anion Transporters - drug effects ; Organic Anion Transporters - metabolism ; Piperidines - metabolism ; Piperidines - pharmacology ; Pravastatin - metabolism ; Pravastatin - pharmacology ; Pyrimidines - metabolism ; Pyrimidines - pharmacology ; Quinolines - metabolism ; Quinolines - pharmacology ; Rats ; Rosuvastatin Calcium ; Species Specificity ; Sulfonamides - metabolism ; Sulfonamides - pharmacology ; Tetrazoles - metabolism ; Tetrazoles - pharmacology ; Valine - analogs & derivatives ; Valine - metabolism ; Valine - pharmacology ; Valsartan
Is Part Of: Drug metabolism and disposition, 2012-09, Vol.40 (9), p.1744-1756
Description: Interindividual variability in activity of uptake transporters is evident in vivo, yet limited data exist in vitro, confounding in vitro-in vivo extrapolation. The uptake kinetics of seven organic anion-transporting polypeptide substrates was investigated over a concentration range in plated cryopreserved human hepatocytes. Active uptake clearance (CL(active, u)), bidirectional passive diffusion (P(diff)), intracellular binding, and metabolism were estimated for bosentan, pitavastatin, pravastatin, repaglinide, rosuvastatin, telmisartan, and valsartan in HU4122 donor using a mechanistic two-compartment model in Matlab. Full uptake kinetics of rosuvastatin and repaglinide were also characterized in two additional donors, whereas for the remaining drugs CL(active, u) was estimated at a single concentration. The unbound affinity constant (K(m, u)) and P(diff) values were consistent across donors, whereas V(max) was on average up to 2.8-fold greater in donor HU4122. Consistency in K(m, u) values allowed extrapolation of single concentration uptake activity data and assessment of interindividual variability in CL(active) across donors. The maximal contribution of active transport to total uptake differed among donors, for example, 85 to 96% and 68 to 87% for rosuvastatin and repaglinide, respectively; however, in all cases the active process was the major contributor. In vitro-in vivo extrapolation indicated a general underprediction of hepatic intrinsic clearance, an average empirical scaling factor of 17.1 was estimated on the basis of seven drugs investigated in three hepatocyte donors, and donor-specific differences in empirical factors are discussed. Uptake K(m, u) and CL(active, u) were on average 4.3- and 7.1-fold lower in human hepatocytes compared with our previously published rat data. A strategy for the use of rat uptake data to facilitate the experimental design in human hepatocytes is discussed.
Publisher: United States: The American Society for Pharmacology and Experimental Therapeutics
Language: English
Identifier: ISSN: 0090-9556
EISSN: 1521-009X
DOI: 10.1124/dmd.112.046193
PMID: 22665271
Source: Geneva Foundation Free Medical Journals at publisher websites
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Use of mechanistic modeling to assess interindividual variability and interspecies differences in active uptake in human and rat hepatocytes

Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics 2012 ;ISSN: 0090-9556 ;EISSN: 1521-009X ;DOI: 10.1124/dmd.112.046193 ;PMID: 22665271

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