Functional characteristics of CYP3A4 allelic variants on the metabolism of loperamide in vitro This article was published in the following Dove Press journal: Infection and Drug Resistance

• Published in: Infection and drug resistance p. 2809
• Main Authors: Lin, Qian-Meng, Li, Ying-Hui, Liu, Qian, Pang, Ni-Hong, Xu, Ren-Ai, Cai, Jian-Ping, Hu, Guo-Xin
• Format: Journal Article
• Language: English
• Published: Dove Medical Press Limited 01-09-2019
• Subjects: Alleles; Cytochrome P-450; Drug resistance; Enzymes; Genetic polymorphisms; Health aspects; Instrument industry (Equipment); Loperamide; Niacinamide; Novels; Phosphates; Purines; United States; China
• ISSN: 1178-6973; 1178-6973
• DOI: 10.2147/IDR.S215129

Background: Cytochrome P450 3A4 (CYP3A4) appears to be genetically polymorphic, which in turn contributes to interindividual variability in response to therapeutic drugs. Loperamide, identified as a CYP3A4 substrate, is prone to misuse and abuse and has high risks of life-threatening cardiotoxicity. Methods: Thus, this study is designed to evaluate the enzymatic characteristics of 29 CYP3A4 alleles toward loperamide in vitro, including the 7 novel CYP3A4 variants (*28-*34). The incubation system (containing CYP3A4 enzyme, cytochrome b5, 0.5-20 [micro]M loperamide, potassium phosphate buffer and nicotinamide adenine dinucleotide phosphate) was subject to 40-mins incubation at 37[degrees]C and the concentrations of N-demethylated loperamide were quantified by UPLC-MS/MS. Results: As a result, CYP3A4.6, .17, .20 and .30 showed extremely low activity or no activity and the rest of CYP3A4 variants presented varying degrees of decrements in catalytical activities when compared with CYP3A4.1. Conclusion: As the first study to identify the properties of these CYP3A4 variants toward loperamide metabolism, our investigation may establish the genotype-phenotype relationship for loperamide, predict an individual's capability in response to loperamide, and provide some guidance of clinical medication and treatment for loperamide. Keywords: CYP3A4, genetic polymorphism, interindividual variability, loperamide, misuse and abuse, cardiotoxicity, personalized treatment