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

Abstract

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 , C and t of aripiprazole were higher and clearance of aripiprazole, AUC of dehydro-aripiprazole and ratio dehydro-aripiprazole/aripiprazole were lower. AUC of aripiprazole of poor metabolizer (PM) subjects was increased by 50% compared to extensive metabolizers (EM), and AUC of dehydro-aripiprazole was decreased by 33%. ABCB1 1236TT subjects had a lower clearance of aripiprazole (p = 0.023) and AUC (p = 0.039) and C 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 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.

Association between aripiprazole pharmacokinetics and CYP2D6 phenotypes: A systematic review and meta-analysis

“…After removing duplicates, we reviewed the remaining 185 articles in the form of title and abstract; 121 citations were excluded after the title and abstract screen. Subsequently, 55 articles were excluded following a full‐text screen, leaving 10 articles eligible for meta‐analysis . The general characteristics of the included studies are summarized in Table .…”

“…The ethnicities included Japanese, Spanish, Dutch, Belgian and Norwegian. CYP2D6 phenotypes were re‐classified according to a unified standard prior to subject inclusion, regardless of the standards used in the original studies. The unified classification standard of the four phenotypes (UM, EM, IM and PM) is described in Table , and the actual variants used to assign CYP2D6 genotypes are shown in Table .…”

“…Owing to its highly polymorphic nature and major contribution to the metabolism and bioactivation of numerous clinically used drugs, CYP2D6 is one of the most extensively studied drug‐metabolizing enzymes . The relationship between CYP2D6 genotype and phenotype has been intensively studied over the past decade; various methods have been used to predict CYP2D6 phenotype based on its genotype . Establishing a unified standard for phenotypic assignment based on genotypic data has been the goal of many researchers in this field .…”

“…Establishing a unified standard for phenotypic assignment based on genotypic data has been the goal of many researchers in this field . As is shown in Table , subjects can be classified into four phenotypes: PMs (carrying two non‐functional alleles), intermediate metabolizers (IMs, harbouring one non‐functional allele and one decreased‐function allele, or two decreased‐function alleles), extensive metabolizers (EMs, carrying one functional allele) or ultra‐rapid metabolizers (UMs, carrying two functional alleles).…”

Effects of aripiprazole on circadian prolactin secretion related to pharmacogenetics in healthy volunteers

“…Thirty‐one healthy volunteers (14 males and 17 females) who participated in 6 bioequivalence clinical trials administering a single dose of aripiprazole were included in the current study . Additionally, 12 healthy volunteers (six males and six females) receiving a single 600‐mg dose of ibuprofen (IBU) were included in the study as controls as it is known to have no effect on prolactin secretion .…”