title: Comparative pharmacokinetics and metabolism studies in lean and diet- induced obese mice: an animal efficacy model for 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitors.
abstract: Diet-induced obese (DIO) mice have been commonly used as an animal model in the efficacy assessment for new drug candidates. Although high-fat feeding has been reported to cause profound physiological changes, including the expression of drug-metabolizing enzymes, limited studies have been reported regarding the effect of obesity/diabetes on pharmacokinetics (PK) in animals. In this study, we investigated PK profiles of three 11 -HSD-1 inhibitors in the DIO mice and compared them to the normal lean mice. After oral administration, the in vivo exposure (AUC) of all three compounds was higher in DIO mice, which was consistent with the observed lower systemic clearance (CL) in DIO mice compared to lean mice. As illustrated by Compound E, a compound metabolized predominantly by CYP3A and 2C, the metabolic profiles for Compound E were qualitatively similar between DIO and lean mice, but quantitatively lower in the DIO mice. Indeed, P-450 activities for CYP3A and 2C as well as 2D were found to be lower in liver microsomes prepared from DIO mice. The calculated hepatic clearance (CLH) from in vitro studies with liver microsomes correlated well with the observed in vivo clearance for both DIO and lean mice. The calculated oral bioavailability (F%) based on intrinsic hepatic clearance (C(LH, int)) predicted ~3 fold increase in F% for the DIO mice, which was comparable to the observed value. Collectively, these data suggest that the higher F% is most likely due to the lower first-pass effect in DIO mice. This study highlights the needs to take caution when extrapolating PK and exposure data from healthy animals to diseased animals in designing pharmacological studies.
authors.affiliation: Discovery Pharmacokinetics, Drug Safety and Metabolism, Wyeth Research, Andover, MA 01810, USA. Mengmeng.Wang@pfizer.com
authors.forename: Mengmeng
authors.initials: M
authors.lastname: Wang
authors.forename: Xianbin
authors.initials: X
authors.lastname: Tian
authors.forename: Louis
authors.initials: L
authors.lastname: Leung
authors.forename: Jianyao
authors.initials: J
authors.lastname: Wang
authors.forename: Nicole
authors.initials: N
authors.lastname: Houvig
authors.forename: Jason
authors.initials: J
authors.lastname: Xiang
authors.forename: Zhao-Kui
authors.initials: ZK
authors.lastname: Wan
authors.forename: Eddine
authors.initials: E
authors.lastname: Saiah
authors.forename: Seung
authors.initials: S
authors.lastname: Hahm
authors.forename: Vipin
authors.initials: V
authors.lastname: Suri
authors.forename: Xin
authors.initials: X
authors.lastname: Xu
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D001682:Biological Availability; D001711:Biotransformation; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004032:Diet; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics*; D006801:Humans; D007275:Injections, Intravenous; D007527:Isoenzymes; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D008657:Metabolic Clearance Rate; D051379:Mice; D008810:Mice, Inbred C57BL; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D008954:Models, Biological; D009765:Obesity / Q000201:enzymology* / Q000209:etiology
chemical_list: D004791:Enzyme Inhibitors; D007527:Isoenzymes; D003577:Cytochrome P-450 Enzyme System; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1