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- Title
Influence of <italic>CYP2D6</italic>,<italic> CYP3A4</italic>,<italic> CYP3A5</italic> and <italic>ABCB1</italic> Polymorphisms on Pharmacokinetics and Safety of Aripiprazole in Healthy Volunteers.
- Authors
Belmonte, Carmen; Ochoa, Dolores; Román, Manuel; Saiz‐Rodríguez, Miriam; Wojnicz, Aneta; Gómez‐Sánchez, Clara Isabel; Martín‐Vílchez, Samuel; Abad‐Santos, Francisco
- Abstract
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. <italic>CYP2D6</italic> (*3,*4,*5,*6,*7,*9 and copy number variations), <italic>CYP3A4</italic> (*20 and *22), <italic>CYP3A5</italic>*3 and C3435T, C1236T and G2677T/A in <italic>ABCB1</italic> gene were determined. As the number of active <italic>CYP2D6</italic> alleles decreased, AUC0−t, <italic>C</italic>max and <italic>t</italic>1/2 of aripiprazole were higher and clearance of aripiprazole, AUC0−t of dehydro‐aripiprazole and ratio dehydro‐aripiprazole/aripiprazole were lower. AUC0−t of aripiprazole of poor metabolizer (PM) subjects was increased by 50% compared to extensive metabolizers (EM), and AUC0−t of dehydro‐aripiprazole was decreased by 33%. <italic>ABCB1</italic> 1236TT subjects had a lower clearance of aripiprazole (<italic>p</italic> = 0.023) and AUC0−t (<italic>p</italic> = 0.039) and <italic>C</italic>max of dehydro‐aripiprazole (<italic>p</italic> = 0.036) compared to C/C. <italic>CYP3A5</italic>*3/*3 subjects had a 10% lower ratio dehydro‐aripiprazole/aripiprazole than *1/*3 (<italic>p</italic> = 0.019). Adverse drug reactions (ADRs) had a directly proportional relationship with AUC0−t of aripiprazole (<italic>p</italic> = 0.001), especially nausea/vomiting, which were more common in women (<italic>p</italic> = 0.005). Women and <italic>CYP3A5</italic>*1/*1 subjects showed more often dizziness (<italic>p</italic> = 0.034; <italic>p</italic> = 0.009). Pharmacokinetics of aripiprazole is affected by <italic>CYP2D6</italic> phenotype but also by sex and C1236T (<italic>ABCB1</italic> gene), while dehydro‐aripiprazole pharmacokinetics is affected by <italic>CYP2D6</italic> and C1236T. The ratio dehydro‐aripiprazole/aripiprazole was influenced by <italic>CYP2D6</italic> phenotype and <italic>CYP3A5</italic>*3. Concentrations of aripiprazole, sex, <italic>CYP3A5</italic>*3 and <italic>CYP2D6</italic> were involved in the development of ADRs.
- Subjects
FIBRINOGEN polymorphisms; CYTOCHROME P-450; PHARMACOKINETICS; GLYCOPROTEINS; ARIPIPRAZOLE
- Publication
Basic & Clinical Pharmacology & Toxicology, 2018, Vol 122, Issue 6, p596
- ISSN
1742-7835
- Publication type
Article
- DOI
10.1111/bcpt.12960