Effect of the most relevant CYP3A4 and CYP3A5 polymorphisms on the pharmacokinetic parameters of 10 CYP3A substrates
Entity
UAM. Departamento de Farmacología; Instituto de Investigación Sanitaria Hospital Universitario de La Paz (IdiPAZ); Instituto de Investigación Sanitaria Hospital Universitario de La Princesa (IIS-IP); Instituto Teófilo Hernando de I+D del Medicamento (ITH)Publisher
MDPI, Basel, SMwitzerlandDate
2020-04-22Citation
10.3390/biomedicines8040094
Biomedicines 8.4 (2020): 1-20
ISSN
2227-9059DOI
10.3390/biomedicines8040094Funded by
F.A.S. and D.O. have been consultants or investigators in clinical trials sponsored by the following pharmaceutical companies: Abbott, Alter, Chemo, Cinfa, FAES, Farmalíder, Ferrer, GlaxoSmithKline, Galenicum, Gilead, Italfarmaco, Janssen-Cilag, Kern, Normon, Novartis, Servier, Silverpharma, Teva and Zambon. M.N.G is co-financed by the European Social Fund and the Youth European Initiative, grant number PEJ-2018-TL/BMD-11080. D.K. is co-financed by the H2020 Marie Sklodowska-Curie Innovative Training Network 721236 grantEditor's Version
http://doi.org/10.3390/biomedicines8040094Subjects
CYP3A4; CYP3A5; Pharmacokinetics; FarmaciaRights
© 2020 The AuthorsAbstract
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.
Files in this item
Google Scholar:Saiz-Rodríguez, Miriam
-
Almenara, Susana
-
Navares-Gómez, Marcos
-
Ochoa Mazarro, María Dolores
-
Román, Manuel
-
Zubiaur, Pablo
-
Koller, Dora
-
Santos, María
-
Mejía, Gina
-
Borobia Pérez, Alberto M.
-
Rodríguez-Antona, Cristina
-
Abad Santos, Francisco
This item appears in the following Collection(s)
Related items
Showing items related by title, author, creator and subject.