Influence of CYP 2D6 , CYP 3A4 , CYP 3A5 and ABCB 1 Polymorphisms on Pharmacokinetics and Safety of Aripiprazole in Healthy Volunteers

• Published in: Basic & clinical pharmacology & toxicology Vol. 122; no. 6; pp. 596 - 605
• Main Authors: Belmonte, Carmen, Ochoa, Dolores, Román, Manuel, Saiz‐Rodríguez, Miriam, Wojnicz, Aneta, Gómez‐Sánchez, Clara Isabel, Martín‐Vílchez, Samuel, Abad‐Santos, Francisco
• Format: Journal Article
• Language: English
• Published: 01.06.2018
• ISSN: 1742-7835; 1742-7843
• DOI: 10.1111/bcpt.12960

The aim of this study was to investigate the effect of polymorphisms in cytochrome P450 ( CYP ) 2D6, CYP 3A4 and CYP 3A5 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 . CYP 2D6 (*3,*4,*5,*6,*7,*9 and copy number variations), CYP 3A4 (*20 and *22), CYP 3A5 *3 and C3435T, C1236T and G2677T/A in ABCB 1 gene were determined. As the number of active CYP 2D6 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%. ABCB 1 1236 TT 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. CYP 3A5 *3/*3 subjects had a 10% lower ratio dehydro‐aripiprazole/aripiprazole than *1/*3 ( p  = 0.019). Adverse drug reactions ( ADR s) 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 CYP 3A5 *1/*1 subjects showed more often dizziness ( p  = 0.034; p  = 0.009). Pharmacokinetics of aripiprazole is affected by CYP 2D6 phenotype but also by sex and C1236T ( ABCB 1 gene), while dehydro‐aripiprazole pharmacokinetics is affected by CYP 2D6 and C1236T. The ratio dehydro‐aripiprazole/aripiprazole was influenced by CYP 2D6 phenotype and CYP 3A5 *3. Concentrations of aripiprazole, sex, CYP 3A5 *3 and CYP 2D6 were involved in the development of ADR s.