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

Mengmeng      Wang; Xianbin      Tian; Louis      Leung; Jianyao      Wang; Nicole      Houvig; Jason      Xiang; Eddine      Saiah; Seung      Hahm; Vipin      Suri; Xin      Xu

doi:10.2174/187231211794455280

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 11β-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 (CLH, 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.

Keywords: 11β-HSD-1, cytochrome P450, DIO mice, pharmacokinetics, strain difference, drug-metabolizing enzymes, CYP3A, liver, crosomes, intrinsic hepatic clearance, Type II diabetes, hepatic stea-tosis, hypertension, drug-drug interactions, anti-obesity agents, glucocorticoid, visceral obesity, Cushing syndrome, glucose intolerance, sulfonamides, amides, triazoles, lactams, piperazine, chromatographic analysis, carnitine acetyltrans-ferase, midazolam, diclofenac, glutathione (GSH), uridine diphosphate glucuronic acid (UDPGA), methylcellulose, cytosol, sodium dithionite, acetyl CoA, acetonitrile, ketoconazole, quinidine, sulfaphenazole, tranylcypromine, naphthoflavone, quercetin, bufuralol, High-performance liquid chromatography, mass spectrometric analysis, mass spectrometer, elec-trospray ionization, hepatic intrinsic clearance, plasma concentration-time pro-files, bioavailability, Mass spectra, N-Dealkylation, piperazinyl, phenotyping study, constitutive an-drostane receptor, blood flow, lipophilicity, permeability, protein binding, hepatic extraction ratio