title: Role of hepatic blood flow and metabolism in the pharmacokinetics of ten drugs in lean, aged and obese rats.
abstract: 1. The effect of age and obesity on the pharmacokinetics (PK), hepatic blood flow (HBF) and liver metabolism of 10 compounds was determined in rats. The animals fed a high-fat diet were defined as the diet-induced obese (DIO) group, while the animals that were aged similar to the DIO rats but not fed with high-fat diet were called the age-matched (AM) group. 2. The clearance (CL) values of high CL compounds (CL > 50 mL/min/kg, namely propranolol, diazepam, phenytoin, ethinylestradiol, lorcaserin and fenfluramine) decreased significantly (1.5- to 6-fold) in DIO and AM rats as compared to lean rats, while there was no clear trend for change in CL for the low-to-moderate CL compounds (CL < 50 mL/min/kg, namely atenolol, chlorzoxazone, vancomycin and sibutramine). Hepatocytes incubations revealed a change in half life (t1/2) only for phenytoin. The body weight normalized liver weights and HBF of AM and DIO rats were found to be 2- to 3-fold lower than in lean rats. 3. Our findings suggest that age, and diet to a lesser extent, can reduce HBF and body normalized liver weights and, hence, also reduce CL values for high CL compounds in rats.
authors.affiliation: Pharmaceutical Candidate Optimization, Biocon Bristol-Myers Squibb Research and Development Center (BBRC), Syngene International Limited , Bangalore, Karnataka , India .
authors.forename: Murali
authors.initials: M
authors.lastname: Subramanian
authors.forename: Vishwanath
authors.initials: V
authors.lastname: Kurawattimath
authors.forename: Krishna
authors.initials: K
authors.lastname: Pocha
authors.forename: Chris
authors.initials: C
authors.lastname: Freeden
authors.forename: Indranil
authors.initials: I
authors.lastname: Rao
authors.forename: T Thanga
authors.initials: TT
authors.lastname: Mariappan
authors.forename: Punit H
authors.initials: PH
authors.lastname: Marathe
authors.forename: Reeba K
authors.initials: RK
authors.lastname: Vikramadithyan
authors.forename: Pamela
authors.initials: P
authors.lastname: Abraham
authors.forename: Chetan P
authors.initials: CP
authors.lastname: Kulkarni
authors.forename: Prasanna
authors.initials: P
authors.lastname: Katnapally
authors.forename: Ravikumar
authors.initials: R
authors.lastname: Nutakki
authors.forename: Sundeep
authors.initials: S
authors.lastname: Paruchury
authors.forename: Priyadeep
authors.initials: P
authors.lastname: Bhutani
authors.forename: Sandhya
authors.initials: S
authors.lastname: Mandlekar
mesh_terms: D000375:Aging / Q000502:physiology*; D000818:Animals; D002478:Cells, Cultured; D004041:Dietary Fats / Q000009:adverse effects; D006207:Half-Life; D022781:Hepatocytes / Q000378:metabolism; D008099:Liver / Q000098:blood supply* / Q000378:metabolism*; D009765:Obesity / Q000209:etiology / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D004041:Dietary Fats
keywords: Altered clearance; CYP2E1; diet-induced obesity; efficacy models; hepatic blood flow; metabolism; pharmacokinetics; urinary clearance