Argikar, Upendra, Potter, Phil, Matthew, Hutzler and Punit, Marathe (2016) Challenges and Opportunities with Non-CYP Enzymes Aldehyde oxidase, Carboxyl esterase and UDP-glucuronosyl transferase. Focus on Reaction Phenotyping and Prediction of Human Clearance. AAPS Journal, 18 (6). pp. 1391-1405. ISSN N/A

Abstract

Over the years, drug metabolism scientists have made significant progress in reducing metabolic instability due to cytochrome P450-mediated oxidation. High throughput metabolic stability screening assays have been successful in eliminating compounds with high metabolic turnover in liver microsomes, hence compounds with little to no oxidative metabolism advance further in lead optimization. Furthermore, high lipophilicity and low aqueous solubility of presently pursued chemotypes reduces the probability of renal excretion. As such, these low microsomal turnover compounds are often substrates for glucuronidation (and other Phase II metabolism) and other non CYP-mediated metabolism (hydrolysis, other oxidative pathways). UGTs, esterases and aldehyde oxidase (AO) are major enzymes involved in catalyzing such metabolism. Hepatocytes provide an excellent tool to identify such non CYP-mediated pathways. Usually, the elucidation of major metabolites formed in hepatocytes provides some assessment of the enzymes involved. Such enzymes then become major metabolic routes and clearance pathways in animals and humans. The accurate prediction of hepatic (Fh) and intestinal availability (Fg) is vital for determining human pharmacokinetics. To predict these PK parameters for P450-mediated metabolism, in vitro–in vivo extrapolation (IVIVE) using hepatic microsomes, hepatocytes, and intestinal microsomes has been actively investigated. However, IVIVE has not been sufficiently evaluated for non-P450 enzymes. The predictive nature of these reactions as a mechanism of elimination is not well understood across species, albeit rodents are generally poor models to predict human Phase II metabolism, esterase-mediated hydrolysis as well as AO-mediated oxidation and clearance. In addition to the involvement of liver, extra-hepatic enzymes (intestine, kidney, lung) are also likely to contribute to these pathways. While there has been considerable progress in predicting metabolic pathways and clearance primarily mediated by the liver, progress in characterizing extra-hepatic metabolism and prediction of clearance has been slow. Well-characterized in vitro systems or in vivo animal models to assess drug-drug interaction potential and inter-subject variability due to polymorphism are not available. Here we focus on the utility of appropriate in vitro studies to characterize non CYP-mediated metabolism; understand the enzymes involved followed by pharmacokinetic studies in the appropriately characterized surrogate species. The review will highlight progress made in establishing in vitro-in vivo correlation; predicting human clearance and avoid costly clinical failures when non-CYP mediated metabolic pathways are predominant.

Item Type:	Article
Date Deposited:	09 Nov 2016 00:45
Last Modified:	09 Nov 2016 00:45
URI:	https://oak.novartis.com/id/eprint/29254