Evaluation of the pharmacokinetics, biotransformation and hepatic transporter effects of troglitazone in mice with humanized livers.
The pharmacokinetics, biotransformation and hepatic transporter effects of troglitazone were investigated following daily oral dosing, at 300 and 600 mg/kg, for 7 days to control (SCID) and chimeric (PXB) mice with humanized livers.        Clinical chemistry revealed no consistent pattern of changes associated with troglitazone treatment in the PXB mouse. Human MRP2 but not mouse mrp2 was down-regulated following troglitazone treatment. Pharmacokinetic analysis revealed similar T(max) values for troglitazone in both mouse groups, a mono- and bi-phasic elimination phase in PXB and SCID mice, respectively, but a 3- to 5- and 2- to 5-fold higher C(max) and AUC, respectively, in PXB mice.        Oxidative and conjugative metabolic pathways were identified, with the sulfate being the predominant metabolite in PXB compared to SCID mice (4- to 13-fold increase in liver and blood, respectively). The glucuronide conjugate was predominant in SCID mice. There was no evidence of glutathione conjugation. The primary oxidative pathways were mono- and di-oxidations which may also be attributed to quinone or hydroquinone derivatives. Several metabolites were observed in PXB mice only.        As the troglitazone metabolic profiles in the PXB mouse were similar to reported human data the PXB mouse model can provide a useful first insight into circulating human metabolites of xenobiotics metabolized in the liver.
Drug Metabolism and Pharmacokinetics IM, Alderley Park, AstraZeneca UK Ltd, Macclesfield, Cheshire, UK.
Timothy
T
Schulz-Utermoehl
Sunil
S
Sarda
John R
JR
Foster
Matt
M
Jacobsen
J Gerry
JG
Kenna
Yoshio
Y
Morikawa
Juuso
J
Salmu
Gerhard
G
Gross
Ian D
ID
Wilson
D000818:Animals; D002839:Chromans / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology*; D005260:Female; D022781:Hepatocytes / Q000637:transplantation*; D006801:Humans; D007004:Hypoglycemic Agents; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D016513:Mice, SCID; D000089762:Multidrug Resistance-Associated Protein 2; D010084:Oxidation-Reduction; D013431:Sulfates / Q000378:metabolism; D045162:Thiazolidinediones / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology*; D018183:Transplantation Chimera; D014183:Transplantation, Heterologous; D000077288:Troglitazone
C000715087:ABCC2 protein, human; D002839:Chromans; D007004:Hypoglycemic Agents; D000089762:Multidrug Resistance-Associated Protein 2; D013431:Sulfates; D045162:Thiazolidinediones; D000077288:Troglitazone