Influence of CYP2D6, CYP3A4, CYP3A5 and ABCB1 Polymorphisms on Pharmacokinetics and Safety of Aripiprazole in Healthy Volunteers.

Autor: Belmonte C; Clinical Pharmacology Department, Hospital Universitario de la Princesa, Instituto Teofilo Hernando, Instituto de Investigacion Sanitaria Princesa (IP), Madrid, Spain.; UICEC Hospital Universitario de la Princesa, Plataforma SCReN (Spanish Clinical Reseach Network), Instituto de Investigacion Sanitaria la Princesa (IP), Madrid, Spain., Ochoa D; Clinical Pharmacology Department, Hospital Universitario de la Princesa, Instituto Teofilo Hernando, Instituto de Investigacion Sanitaria Princesa (IP), Madrid, Spain.; UICEC Hospital Universitario de la Princesa, Plataforma SCReN (Spanish Clinical Reseach Network), Instituto de Investigacion Sanitaria la Princesa (IP), Madrid, Spain., Román M; Clinical Pharmacology Department, Hospital Universitario de la Princesa, Instituto Teofilo Hernando, Instituto de Investigacion Sanitaria Princesa (IP), Madrid, Spain.; UICEC Hospital Universitario de la Princesa, Plataforma SCReN (Spanish Clinical Reseach Network), Instituto de Investigacion Sanitaria la Princesa (IP), Madrid, Spain., Saiz-Rodríguez M; Clinical Pharmacology Department, Hospital Universitario de la Princesa, Instituto Teofilo Hernando, Instituto de Investigacion Sanitaria Princesa (IP), Madrid, Spain., Wojnicz A; Clinical Pharmacology Department, Hospital Universitario de la Princesa, Instituto Teofilo Hernando, Instituto de Investigacion Sanitaria Princesa (IP), Madrid, Spain., Gómez-Sánchez CI; Department of Genetics, IIS-Fundacion Jimenez Dıaz University Hospital (IIS-FJD, UAM), Madrid, Spain., Martín-Vílchez S; Clinical Pharmacology Department, Hospital Universitario de la Princesa, Instituto Teofilo Hernando, Instituto de Investigacion Sanitaria Princesa (IP), Madrid, Spain., Abad-Santos F; Clinical Pharmacology Department, Hospital Universitario de la Princesa, Instituto Teofilo Hernando, Instituto de Investigacion Sanitaria Princesa (IP), Madrid, Spain.; UICEC Hospital Universitario de la Princesa, Plataforma SCReN (Spanish Clinical Reseach Network), Instituto de Investigacion Sanitaria la Princesa (IP), Madrid, Spain.; Center for Biomedical Research Network Hepatic and Liver diseases (CIBERedh) - Instituto de Salud Carlos III, Madrid, Spain.
Jazyk: angličtina
Zdroj: Basic & clinical pharmacology & toxicology [Basic Clin Pharmacol Toxicol] 2018 Jun; Vol. 122 (6), pp. 596-605. Date of Electronic Publication: 2018 Feb 22.
DOI: 10.1111/bcpt.12960
Abstrakt: The aim of this study was to investigate the effect of polymorphisms in cytochrome P450 (CYP) 2D6, CYP3A4 and CYP3A5 enzymes and in P-glycoprotein (P-gp) on the pharmacokinetics and safety of aripiprazole and, its active metabolite, dehydro-aripiprazole, in 148 healthy volunteers from six bioequivalence trials receiving a single oral dose of aripiprazole. The plasma concentrations of both analytes were measured by LC-MS/MS. CYP2D6 (*3,*4,*5,*6,*7,*9 and copy number variations), CYP3A4 (*20 and *22), CYP3A5*3 and C3435T, C1236T and G2677T/A in ABCB1 gene were determined. As the number of active CYP2D6 alleles decreased, AUC 0-t , C max and t 1/2 of aripiprazole were higher and clearance of aripiprazole, AUC 0-t of dehydro-aripiprazole and ratio dehydro-aripiprazole/aripiprazole were lower. AUC 0-t of aripiprazole of poor metabolizer (PM) subjects was increased by 50% compared to extensive metabolizers (EM), and AUC 0-t of dehydro-aripiprazole was decreased by 33%. ABCB1 1236TT subjects had a lower clearance of aripiprazole (p = 0.023) and AUC 0-t (p = 0.039) and C max of dehydro-aripiprazole (p = 0.036) compared to C/C. CYP3A5*3/*3 subjects had a 10% lower ratio dehydro-aripiprazole/aripiprazole than *1/*3 (p = 0.019). Adverse drug reactions (ADRs) had a directly proportional relationship with AUC 0-t of aripiprazole (p = 0.001), especially nausea/vomiting, which were more common in women (p = 0.005). Women and CYP3A5*1/*1 subjects showed more often dizziness (p = 0.034; p = 0.009). Pharmacokinetics of aripiprazole is affected by CYP2D6 phenotype but also by sex and C1236T (ABCB1 gene), while dehydro-aripiprazole pharmacokinetics is affected by CYP2D6 and C1236T. The ratio dehydro-aripiprazole/aripiprazole was influenced by CYP2D6 phenotype and CYP3A5*3. Concentrations of aripiprazole, sex, CYP3A5*3 and CYP2D6 were involved in the development of ADRs.
(© 2018 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)
Databáze: MEDLINE
Externí odkaz:
Nepřihlášeným uživatelům se plný text nezobrazuje