Hepatobiliary disposition of troglitazone and metabolites in rat and human sandwich-cultured hepatocytes: use of Monte Carlo simulations to assess the impact of changes in biliary excretion on troglitazone sulfate accumulation.
This study examined the hepatobiliary disposition of troglitazone (TGZ) and metabolites [TGZ sulfate (TS), TGZ glucuronide (TG), and TGZ quinone (TQ)] over time in rat and human sandwich-cultured hepatocytes (SCH). Cells were incubated with TGZ; samples were analyzed for TGZ and metabolites by liquid chromatography-tandem mass spectrometry. SCH mimicked the disposition of TGZ/metabolites in vivo in rats and humans; TGZ was metabolized primarily to TS and to a lesser extent to TG and TQ. In human SCH, the biliary excretion index (BEI) was negligible for TGZ and TQ, approximately 16% for TS, and approximately 43% for TG over the incubation period; in rat SCH, the BEI for TS and TG was approximately 13 and approximately 41%, respectively. Hepatocyte accumulation of TS was extensive, with intracellular concentrations ranging from 132 to 222 microM in rat SCH; intracellular TGZ concentrations ranged from 7.22 to 47.7 microM. In human SCH, intracellular TS and TGZ concentrations ranged from 136 to 160 microM and from 49.4 to 84.7 microM, respectively. Pharmacokinetic modeling and Monte Carlo simulations were used to evaluate the impact of modulating the biliary excretion rate constant (K(bile)) for TS on TS accumulation in hepatocytes and medium. Simulations demonstrated that intracellular concentrations of TS may increase up to 3.1- and 5.7-fold when biliary excretion of TS was decreased 2- and 10-fold, respectively. It is important to note that altered hepatobiliary transport and the extent of hepatocyte exposure may not always be evident based on medium concentrations (analogous to systemic exposure in vivo). Pharmacokinetic modeling/simulation with data from SCH is a useful approach to examine the impact of altered hepatobiliary transport on hepatocyte accumulation of drug/metabolites.
Division of Pharmacotherapy and Experimental Therapeutics, The University of North Carolina at Chapel Hill Eshelman School of Pharmacy, North Carolina 27599-7360, USA.
Jin Kyung
JK
Lee
Tracy L
TL
Marion
Koji
K
Abe
Changwon
C
Lim
Gary M
GM
Pollock
Kim L R
KL
Brouwer
D000328:Adult; D000818:Animals; D001646:Bile / Q000378:metabolism*; D018929:Cell Culture Techniques; D002478:Cells, Cultured; D002839:Chromans / Q000378:metabolism* / Q000493:pharmacokinetics; D002853:Chromatography, Liquid; D003198:Computer Simulation; D005260:Female; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007004:Hypoglycemic Agents / Q000378:metabolism* / Q000493:pharmacokinetics; D008099:Liver / Q000378:metabolism*; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D008954:Models, Biological; D009010:Monte Carlo Method; D047495:PPAR gamma / Q000819:agonists; D051381:Rats; D017208:Rats, Wistar; D053719:Tandem Mass Spectrometry; D045162:Thiazolidinediones / Q000378:metabolism* / Q000493:pharmacokinetics; D014018:Tissue Distribution; D000077288:Troglitazone
D002839:Chromans; D007004:Hypoglycemic Agents; D047495:PPAR gamma; D045162:Thiazolidinediones; D000077288:Troglitazone