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. 2019 Sep 10:12:2809-2817.
doi: 10.2147/IDR.S215129. eCollection 2019.

Functional characteristics of CYP3A4 allelic variants on the metabolism of loperamide in vitro

Qian-Meng Lin  1 , Ying-Hui Li  1 , Qian Liu  1 , Ni-Hong Pang  1 , Ren-Ai Xu  2 , Jian-Ping Cai  3 , Guo-Xin Hu  1
Affiliations

Functional characteristics of CYP3A4 allelic variants on the metabolism of loperamide in vitro

Qian-Meng Lin et al. Infect Drug Resist. .

Abstract

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 μM loperamide, potassium phosphate buffer and nicotinamide adenine dinucleotide phosphate) was subject to 40-mins incubation at 37°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; cardiotoxicity; genetic polymorphism; interindividual variability; loperamide; misuse and abuse; personalized treatment.

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Conflict of interest statement

The authors report no conflicts of interest in this work.

Figures

Figure 1
Figure 1
The transformation of loperamide to its main metabolite N-demethylated loperamide (DLOP).
Figure 2
Figure 2
UPLC-MS/MS chromatographs of N-demethylated loperamide and midazolam (10 μg/mL midazolam) in the 200-μL incubation system: (A) without loperamide and midazolam; (B) with activity-abolished microsomes and spiked with 0.25 μM N-demethylated loperamide; (C) incubating with 20 μM loperamide and 1 pmol CYP3A4.1. Abbreviations: CYP3A4, cytochrome P450 3A4; MRM, multiple reaction monitoring.
Figure 3
Figure 3
Michaelis–Menten curve of the enzymatic activities of the wild-type CYP3A4 and other CYP3A4 variants on loperamide metabolism. Data are presented as mean ± SD of 3 parallel experiments. The variants with designated allele names have been arranged into 6 groups (A–F). Abbreviation: CYP3A4, cytochrome P450 3A4.
Figure 4
Figure 4
Relative clearance of CYP3A4 variants toward loperamide metabolism compared with the wild type, arranged in the order. Notes: Significant differences between the wild-type CYP3A4 and CYP3A4 variants analyzed by the mean of one-way ANOVA with Dunnett’s test, *P<0.05, **P<0.01. Abbreviation: CYP3A4, cytochrome P450 3A4.
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