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Open AccessArticle

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

Clinical Pharmacology Department, Hospital Universitario de La Princesa, Instituto Teófilo Hernando, Universidad Autónoma de Madrid (UAM), Instituto de Investigación Sanitaria La Princesa (IP), 28006 Madrid, Spain
Reseach Unit, Fundación Burgos por la Investigación de la Salud, Hospital Universitario de Burgos, 09006 Burgos, Spain
UICEC Hospital Universitario de la Princesa, Plataforma SCReN (Spanish Clinical Reseach Network), Instituto de Investigación Sanitaria la Princesa (IP), 28006 Madrid, Spain
Centro Nacional de Investigaciones Oncológicas (CNIO), 28029 Madrid, Spain
Clinical Pharmacology Department, Hospital Universitario La Paz, 28029 Madrid, Spain
Pharmacology Department, School of Medicine, Universidad Autónoma de Madrid, 28029 Madrid, Spain
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Biomedicines 2020, 8(4), 94;
Received: 25 March 2020 / Revised: 16 April 2020 / Accepted: 20 April 2020 / Published: 22 April 2020
(This article belongs to the Section Therapeutic Strategies in Different Diseases)
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. View Full-Text
Keywords: CYP3A4; CYP3A5; pharmacokinetics CYP3A4; CYP3A5; pharmacokinetics
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Saiz-Rodríguez, M.; Almenara, S.; Navares-Gómez, M.; Ochoa, D.; Román, M.; Zubiaur, P.; Koller, D.; Santos, M.; Mejía, G.; Borobia, A.M.; Rodríguez-Antona, C.; Abad-Santos, F. Effect of the Most Relevant CYP3A4 and CYP3A5 Polymorphisms on the Pharmacokinetic Parameters of 10 CYP3A Substrates. Biomedicines 2020, 8, 94.

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