Role of hepatic blood flow and metabolism in the pharmacokinetics of ten drugs in lean, aged and obese rats. (December 2014)

• Record Type: Journal Article
• Authors: Subramanian, Murali; Kurawattimath, Vishwanath; Pocha, Krishna; Freeden, Chris; Rao, Indranil; Thanga Mariappan, T.; Marathe, Punit H.; Vikramadithyan, Reeba K.; Abraham, Pamela; Kulkarni, Chetan P.; Katnapally, Prasanna; Nutakki, Ravikumar; Paruchury, Sundeep; Bhutani, Priyadeep; Mandlekar, Sandhya
• Is Part Of: Xenobiotica. Volume 44:Number 12(2014:Dec.)
• Page Start: 1108
• Page End: 1116
• Publication Date: 2014-12
• Subjects: Metabolism -- Periodicals; Drugs -- Physiological effect -- Periodicals; Food additives -- Periodicals; Chemicals -- Physiological effect -- Periodicals; Biochemistry -- Periodicals; Pharmaceutical Preparations -- metabolism -- Periodicals; Metabolism -- Periodicals; 574.133
• DOI: 10.3109/00498254.2014.932470
• Languages: English
• ISSNs: 0049-8254

Abstract

<abstract> <title>Abstract</title> <p>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.</p> <p>2. The clearance (CL) values of high CL compounds (CL &gt; 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 &lt; 50 mL/min/kg, namely atenolol, chlorzoxazone, vancomycin and sibutramine). Hepatocytes incubations revealed a change in half life (<italic>t</italic>_1/2) 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.</p> <p>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.</p> </abstract>