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Challenges and Opportunities with Non-CYP Enzymes Aldehyde Oxidase, Carboxylesterase, and UDP-Glucuronosyltransferase: Focus on Reaction Phenotyping and Prediction of Human Clearance.
- Source :
-
The AAPS journal [AAPS J] 2016 Nov; Vol. 18 (6), pp. 1391-1405. Date of Electronic Publication: 2016 Aug 05. - Publication Year :
- 2016
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Abstract
- Over the years, significant progress has been made in reducing metabolic instability due to cytochrome P450-mediated oxidation. High-throughput metabolic stability screening has enabled the advancement of compounds with little to no oxidative metabolism. 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 non-CYP-mediated metabolism. UGTs, esterases, and aldehyde oxidase are major enzymes involved in catalyzing such metabolism. Hepatocytes provide an excellent tool to identify such pathways including elucidation of major metabolites. To predict human PK parameters for P450-mediated metabolism, in vitro-in vivo extrapolation using hepatic microsomes, hepatocytes, and intestinal microsomes has been actively investigated. However, such methods have not been sufficiently evaluated for non-P450 enzymes. In addition to the involvement of the liver, extrahepatic 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 extrahepatic 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 intersubject variability due to polymorphism are not available. Here we focus on the utility of appropriate in vitro studies to characterize non-CYP-mediated metabolism and to 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 avoiding costly clinical failures when non-CYP-mediated metabolic pathways are predominant.
- Subjects :
- Aldehyde Oxidase chemistry
Animals
Carboxylesterase chemistry
Forecasting
Glucuronosyltransferase chemistry
Humans
Pharmaceutical Preparations chemistry
Pharmaceutical Preparations metabolism
Aldehyde Oxidase metabolism
Carboxylesterase metabolism
Glucuronosyltransferase metabolism
Metabolic Clearance Rate physiology
Phenotype
Subjects
Details
- Language :
- English
- ISSN :
- 1550-7416
- Volume :
- 18
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- The AAPS journal
- Publication Type :
- Academic Journal
- Accession number :
- 27495117
- Full Text :
- https://doi.org/10.1208/s12248-016-9962-6