Construction and verification of CYP3A5 gene polymorphisms using a Saccharomyces cerevisiae expression system to predict drug metabolism

Abstract

The present study evaluated the ability of a Saccharomyces cerevisiae expression system to predict the pharmacokinetic (PK) activity of a calcium channel blocker in patients with distinct cytochrome P450 3A5 (CYP3A5) polymorphisms. The blood pressure lowering activity of amlodipine in 57 hypertensive patients with CYP3A51/1, CYP3A51/3, CYP3A54 and CYP3A56 polymorphisms was evaluated by the current study. Subsequently, a Saccharomyces cerevisiae expression system for CYP3A5 gene polymorphisms was constructed to examine the PK activity of CYP3A51/1, CYP3A54 and CYP3A56 polymorphisms. This system was used to predict the PK of amlodipine and was compared with the in vivo data from different gene polymorphism groups. The blood pressure lowering activity of amlodipine in hypertensive patients varied among CYP3A5 polymorphisms. The in vivo results demonstrated that CYP3A56 exhibited the highest metabolic rate, followed by CYP3A51/1, CYP3A54 and CYP3A51/3. The difference between CYP3A56 and CYP3A51/1 was not statistically significant (P=0.5). In accordance with in vivo data, CYP3A51/1 exhibited the highest in vitro metabolic rate, followed by CYP3A56 and CYP3A54. With the exception of the comparison between CYP3A56 and CYP3A51/1, polymorphisms exhibited statistically significant differences compared with CYP3A51/1 (P<0.05). The Saccharomyces cerevisiae expression system may be a cost effective and potentially useful tool for assessing the PK activity of drugs that are metabolized by CYP3A5.