Effect of the Most Relevant CYP3A4 and CYP3A5 Polymorphisms on the Pharmacokinetic Parameters of 10 CYP3A Substrates

Abstract

Several cytochrome P450 (CYP) CYP3A polymorphisms were associated with reduced enzyme function. We aimed to evaluate the influence of these alleles on the pharmacokinetic parameters (PK) of several CYP3A substrates. We included 251 healthy volunteers who received a single dose of ambrisentan, atorvastatin, imatinib, aripiprazole, fentanyl, amlodipine, donepezil, olanzapine, fesoterodine, or quetiapine. The volunteers were genotyped for CYP3A4 and CYP3A5 polymorphisms by qPCR. To compare the PK across studies, measurements were corrected by the mean of each parameter for every drug and were logarithmically transformed. Neither CYP3A phenotype nor individual CYP3A4 or CYP3A5 polymorphisms were significantly associated with differences in PK. However, regarding the substrates that are exclusively metabolized by CYP3A, we observed a higher normalized AUC (p = 0.099) and a tendency of lower normalized Cl (p = 0.069) in CYP3A4 mutated allele carriers what was associated with diminished drug metabolism capacity. CYP3A4 polymorphisms did not show a pronounced influence on PK of the analysed drugs. If so, their impact could be detectable in a very small percentage of subjects. Although there are few subjects carrying CYP3A4 double mutations, the effect in those might be relevant, especially due to the majority of subjects lacking the CYP3A5 enzyme. In heterozygous subjects, the consequence might be less noticeable due to the high inducible potential of the CYP3A4 enzyme.

A Critical Perspective on 3D Liver Models for Drug Metabolism and Toxicology Studies

“…Interindividual variability concerning phase I, II, and III enzyme expression can also justify some cases of hepatotoxicity. Genetic polymorphisms are reported to affect the biotransformation of drugs dependent on CYP2C9, CYP2C19, CYP2B6, CYP2D6, CYP3A4, and CYP3A5 subfamilies, phase II enzymes uridine 5′-diphosphate glucuronosyltransferase (UGT) 1A1, UGT2B7 and N -acetyltransferase (NAT) 2, and hepatic transporters multidrug resistance protein (MDR) 1, breast cancer resistance protein (BCRP), MRPs, and OATP1B1, amongst others ( Wienkers and Heath, 2005 ; Zanger et al, 2007 ; Brockmöller and Tzvetkov, 2008 ; Shah et al, 2015 ; Krasniqi et al, 2016 ; Saiz-Rodríguez et al, 2020 ). Some classical examples include CYP2D6, due to its clinical impact in the bioactivation of drugs such as codeine, tramadol, or tamoxifen within low or extensive metabolizers ( Cavallari et al, 2019 ).…”

Pharmacogenetic Testing of Cytochrome P450 Drug Metabolizing Enzymes in a Case Series of Patients with Prader-Willi Syndrome

“…The distribution of diplotypes finds that the frequency of the wildtype alleles *1A*1A predominates across all PWS genetic subtypes at nearly typical frequency. The occurrence of the reduced function *1*22 diplotype is greater than predicted among all PWS genetic subtypes [ 34 ].…”

“… CYP3A4 allele and diplotype frequencies among PWS DEL ( n = 14), UPD ( n = 15), and combined cohort (ALL PWS, n = 34) compared to Caucasian normative, predicted data [ 33 , 34 ]. …”

Pharmacogenetics of Carbamazepine and Valproate: Focus on Polymorphisms of Drug Metabolizing Enzymes and Transporters

“…CYP3A4 and CYP3A5 show similar structure and substrate specificity. CYP3A5 is highly polymorphic and the presence of CYP3A5 *3 allele (6986A>G, rs776746), the most common nonfunctional variant, influences plasma CBZ levels [ 54 ]. Patients carrying CYP 3A5 *3/*3 had significantly higher levels of CBZ plasma concentration compared to CYP3A5 *1/*1 or CYP3A5 *1/*3 carriers.…”