PMID- 19801447
OWN - NLM
STAT- MEDLINE
DCOM- 20100126
LR  - 20211020
IS  - 1521-0103 (Electronic)
IS  - 0022-3565 (Print)
IS  - 0022-3565 (Linking)
VI  - 332
IP  - 1
DP  - 2010 Jan
TI  - 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.
PG  - 26-34
LID - 10.1124/jpet.109.156653 [doi]
AB  - 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.
FAU - Lee, Jin Kyung
AU  - Lee JK
AD  - Division of Pharmacotherapy and Experimental Therapeutics, The University of 
      North Carolina at Chapel Hill Eshelman School of Pharmacy, North Carolina 
      27599-7360, USA.
FAU - Marion, Tracy L
AU  - Marion TL
FAU - Abe, Koji
AU  - Abe K
FAU - Lim, Changwon
AU  - Lim C
FAU - Pollock, Gary M
AU  - Pollock GM
FAU - Brouwer, Kim L R
AU  - Brouwer KL
LA  - eng
GR  - R56 GM041935/GM/NIGMS NIH HHS/United States
GR  - R01 GM041935/GM/NIGMS NIH HHS/United States
GR  - T32-ES007126/ES/NIEHS NIH HHS/United States
GR  - T32 ES007126/ES/NIEHS NIH HHS/United States
GR  - GM41935/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20091002
PL  - United States
TA  - J Pharmacol Exp Ther
JT  - The Journal of pharmacology and experimental therapeutics
JID - 0376362
RN  - 0 (Chromans)
RN  - 0 (Hypoglycemic Agents)
RN  - 0 (PPAR gamma)
RN  - 0 (Thiazolidinediones)
RN  - I66ZZ0ZN0E (Troglitazone)
SB  - IM
MH  - Adult
MH  - Animals
MH  - Bile/*metabolism
MH  - Cell Culture Techniques
MH  - Cells, Cultured
MH  - Chromans/*metabolism/pharmacokinetics
MH  - Chromatography, Liquid
MH  - Computer Simulation
MH  - Female
MH  - Hepatocytes/drug effects/*metabolism
MH  - Humans
MH  - Hypoglycemic Agents/*metabolism/pharmacokinetics
MH  - Liver/*metabolism
MH  - Male
MH  - Metabolic Clearance Rate
MH  - Middle Aged
MH  - *Models, Biological
MH  - Monte Carlo Method
MH  - PPAR gamma/agonists
MH  - Rats
MH  - Rats, Wistar
MH  - Tandem Mass Spectrometry
MH  - Thiazolidinediones/*metabolism/pharmacokinetics
MH  - Tissue Distribution
MH  - Troglitazone
PMC - PMC2802476
EDAT- 2009/10/06 06:00
MHDA- 2010/01/27 06:00
PMCR- 2011/01/01
CRDT- 2009/10/06 06:00
PHST- 2009/10/06 06:00 [entrez]
PHST- 2009/10/06 06:00 [pubmed]
PHST- 2010/01/27 06:00 [medline]
PHST- 2011/01/01 00:00 [pmc-release]
AID - jpet.109.156653 [pii]
AID - 3540910 [pii]
AID - 10.1124/jpet.109.156653 [doi]
PST - ppublish
SO  - J Pharmacol Exp Ther. 2010 Jan;332(1):26-34. doi: 10.1124/jpet.109.156653. Epub 
      2009 Oct 2.