Effects of Genetic Polymorphisms of CYP2D6, CYP3A5, and ABCB1 on the Steady-State Plasma Concentrations of Aripiprazole and Its Active Metabolite, Dehydroaripiprazole, in Japanese Patients With Schizophrenia

  title={Effects of Genetic Polymorphisms of CYP2D6, CYP3A5, and ABCB1 on the Steady-State Plasma Concentrations of Aripiprazole and Its Active Metabolite, Dehydroaripiprazole, in Japanese Patients With Schizophrenia},
  author={Takeshi Suzuki and Kazuo Mihara and Akifumi Nakamura and Shoko Kagawa and Goyo Nagai and Kenji Nemoto and Tsuyoshi Kondo},
  journal={Therapeutic Drug Monitoring},
Background: We studied the effects of various factors, including genetic polymorphisms of the cytochrome P450 (CYP) 2D6, CYP3A5, and ABCB1, age, gender, and smoking habit on the steady-state plasma concentrations of aripiprazole and its active metabolite, dehydroaripiprazole, in 89 patients with schizophrenia (46 males, 43 females). Methods: All patients had been receiving fixed doses of aripiprazole for at least 2 weeks. The daily doses were 24 mg (n = 56) and 12 mg (n = 33). No other drugs… 

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

Concentrations of aripiprazole, sex, CYP3A5*3 and CYP2D6 were involved in the development of ADRs, while dehydro‐aripiprazoles pharmacokinetics is affected by CYP 2D6 and C1236T.

The Influence of the CYP3A4*22 Polymorphism and CYP2D6 Polymorphisms on Serum Concentrations of Aripiprazole, Haloperidol, Pimozide, and Risperidone in Psychiatric Patients.

Heterozygous presence of CYP3A4*22 does not increase serum levels of antipsychotics metabolized by both CYP 3A4 and CYP2D6, whereas CYP1D6 polymorphisms do affect serum levels to a limited extent, although a multiple regression analysis showed that only 4% to 17% of the variation in these concentrations could be explained by CYP 2D6 status.

Phenoconversion of CYP2D6 by inhibitors modifies aripiprazole exposure

Patients’ CYP2D6 genotype and co-medication with CYP 2D6 inhibitors can be considered to be the major determinants of aripiprazole pharmacokinetics, and taking into account CYP3A4 expression in aripIPrazole metabolism did not predominate even in the patients with nonfunctional CYP1D6 alleles.

The predictive value of ABCB1, ABCG2, CYP3A4/5 and CYP2D6 polymorphisms for risperidone and aripiprazole plasma concentrations and the occurrence of adverse drug reactions

Information obtained on ABCB1 and ABCG2 gene variants may result useful to tailor treatments with these drugs in Caucasian pediatric patients.

Effects of CYP2C19 and CYP2D6 gene variants on escitalopram and aripiprazole treatment outcome and serum levels: results from the CAN-BIND 1 study

The results showed that amongst patients on ESC-Only, CYP2C19 intermediate and poor metabolizer groups, with reduced or null enzyme function, trended towards significantly lower symptom improvement during Phase II compared to normal metabolizers (NMs), which was not observed in ESC + ARI.

Association of CYP2C19 and CYP2D6 Poor and Intermediate Metabolizer Status With Antidepressant and Antipsychotic Exposure: A Systematic Review and Meta-analysis.

In this systematic review and meta-analysis, the association between CYP2C19/CYP2D6 genotype and drug levels of several psychiatric drugs was quantified with sufficient precision as to be useful as a scientific foundation for CYP 2D6/Cyp2C 19 genotype-based dosing recommendations.

Effects of aripiprazole on pupillometric parameters related to pharmacokinetics and pharmacogenetics after single oral administration to healthy subjects

Aripiprazole affects pupil contraction, which could be a secondary effect through dopamine and serotonin receptors, which is a useful tool to assess autonomic nervous system activity during antipsychotic treatment.

Genetic Polymorphisms Associated With the Pharmacokinetics, Pharmacodynamics and Adverse Effects of Olanzapine, Aripiprazole and Risperidone

Polymorphisms in these genes and other enzymes and transporters, such as enzymes from the uridine 5'-diphospho-glucuronosyltransferase (UGT) family and ATP-binding cassette sub-family B member 1 (ABCB1), are associated to differences in pharmacokinetics are listed.

Effect of ABCB1 C3435T Polymorphism on Pharmacokinetics of Antipsychotics and Antidepressants

The results suggest that P‐glycoprotein polymorphisms could affect CNS drugs disposition, but the genetic factor that alters its activity is still unknown.



Effects of the CYP2D6*10 Allele on the Steady-State Plasma Concentrations of Aripiprazole and Its Active Metabolite, Dehydroaripiprazole, in Japanese Patients With Schizophrenia

It is suggested that the CYP2D6*10(*10) allele plays an important role in controlling the steady-state plasma concentrations of aripiprazole and the sum of a Ripiprazoles and dehydroaripiprazol in Asian subjects.

Impact of the CYP2D6 genotype on steady-state serum concentrations of aripiprazole and dehydroaripiprazole

It is demonstrated that serum concentrations of both ARI and the active sum of ARI + DARI in psychiatric patients were significantly affected by CYP2D6 genotype, which typically needs 30–40% lower doses to achieve a similar steady-state serum concentration as EMs.

Serum Concentrations of Risperidone and Aripiprazole in Subgroups Encoding CYP2D6 Intermediate Metabolizer Phenotype

Serious variability in serum concentrations of risperidone and aripiprazole between CYP2D6 genotypes associated with IM phenotype was revealed and a considerable phenotypical difference was observed between patients carrying 1 and 2 variant alleles.

Influence of itraconazole co-administration and CYP2D6 genotype on the pharmacokinetics of the new antipsychotic ARIPIPRAZOLE.

The urinary 6beta-hydroxycortisol/ cortisol concentration ratio following ITz administration for 7 consecutive days was about half of that before the start of ITZ administration, indicating that CYP3A4 metabolic activity was inhibited by administration of ITz.

Functional Characterization of 17 CYP2D6 Allelic Variants (CYP2D6.2, 10, 14A–B, 18, 27, 36, 39, 47–51, 53–55, and 57)

Functional characterization of 17 CYP2D6 variants revealed an absence of enzyme activity in four, low activity in eight, and high activity in one compared with the wild type, which can be useful for predicting CYP1D6 phenotypes and could be applied to personalized drug therapy.

CYP3A5 genotype has significant effect on quinine 3-hydroxylation in Tanzanians, who have lower total CYP3A activity than a Swedish population

A significant association is noted between CYP3A5 genotype and quinine 3-hydroxylation in Tanzanians, indicating a significant contribution of CYP 3A5 to total 3A activity.

The genetic determinants of the CYP3A5 polymorphism.

Investigation of the expression of CYP3A5 and its genetic determinants in a panel of 183 Caucasian liver samples reports that a SNP within intron 3 (g.6986G>A) is the primary cause of the CYP4A5 protein polymorphism, and should add to efforts to identify clinically relevant, CYP2A5-specific reactions and to further elucidate traits responsible for variable expression of the entire CYP 3A family.

Genetic analysis of the Chinese cytochrome P4502D locus: characterization of variant CYP2D6 genes present in subjects with diminished capacity for debrisoquine hydroxylation.

Important interethnic differences exist in the structure of the CYP2D locus, and they suggest that the frequent distribution of the C188-->T mutation among the CYp2D6Ch genes explains the lower capacity among Chinese to metabolize drugs that are substrates of CYP 2D6, such as antidepressants and neuroleptic agents.

Pharmacokinetics of aripiprazole, a new antipsychotic, following oral dosing in healthy adult Japanese volunteers: influence of CYP2D6 polymorphism.

It is revealed that there is no clear ethnic difference between Japanese and Western subjects in terms of mean plasma PK, while the CYP2D6*10 allele distinctive to Asian populations influences the PK of aripiprazole, and observations suggest that the CYp2D 6*41 allele significantly affects drug-metabolizing activity.

Metabolism of atypical antipsychotics: involvement of cytochrome p450 enzymes and relevance for drug-drug interactions.

Several of atypical antipsychotics are metabolized by CYP enzymes, and physicians should be aware of coadministered drugs that may inhibit or induce these CYp enzymes; examples of such possible interactions are presented.