Quinidine inhibits the 7-hydroxylation of chlorpromazine in extensive metabolisers of debrisoquine

IntroductionClopidogrel is an antiplatelet agent that is widely used for the secondary prevention of cardiovascular and cerebrovascular events. The genotype of cytochrome P450 2C19 (CYP2C19) differentially affects the liver’s metabolism of clopidogrel, which may influence the drug’s response and efficacy for cardiovascular event prevention. In contrast to prior studies of patients with coronary artery diseases, little is known about whether the CYP2C19 genotype influences the preventive efficacy of clopidogrel in patients who had a stroke. We hypothesise that, among patients who had an acute ischaemic stroke who are prescribed clopidogrel, the patients with a loss-of-function CYP2C19 genotype (poor and intermediate metabolisers) may be at a higher risk of composite cardiovascular events than those who are non-carriers (extensive metabolisers).Methods and analysisThis prospective observational multicentre study was designed to determine whether composite cardiovascular events would differ among patients who had an ischaemic stroke prescribed clopidogrel according to CYP2C19 genotype (poor or intermediate vs extensive metabolisers). Inclusion criteria were patients who had an acute ischaemic stroke who underwent CYP2C19 genotype evaluation and received clopidogrel within 72 hours of stroke onset. The primary outcome is composite cardiovascular events (stroke, myocardial infarction, or cardiovascular death) within 6 months after acute ischaemic stroke between patients categorised as poor or intermediate metabolisers and those categorised as extensive metabolisers according to their CYP2C19 genotype.Ethics and disseminationThe Institutional Review Board of Severance Hospital, Yonsei University College of Medicine approved this study (3-2019-0195). We received study approval from the institutional review board of each participating hospital. We plan to disseminate our findings at relevant conferences and meetings and through peer-reviewed journals.Trial registration numberNCT04072705.

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DNA haplotype-dependent differences in the amino acid sequence of debrisoquine 4-hydroxylase (CYP2D6): evidence for two major allozymes in extensive metabolisers

Human Genetics ◽

10.1007/bf00201601 ◽

1994 ◽

Vol 94 (4) ◽

Cited By ~ 21

Author(s):

S. Panserat ◽

C. Mura ◽

N. G�rard ◽

M. Vincent-Viry ◽

M.M. Galteau ◽

...

Keyword(s):

Amino Acid ◽

Amino Acid Sequence ◽

Extensive Metabolisers

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CYP2D6 phenotype and ABCB1 haplotypes are associated with antipsychotic safety in adolescents experiencing acute psychotic episodes

Drug Metabolism and Personalized Therapy ◽

10.1515/dmdi-2021-0124 ◽

2021 ◽

Vol 0 (0) ◽

Author(s):

Dmitriy V. Ivashchenko ◽

Daria A. Yudelevich ◽

Nina I. Buromskaya ◽

Pavel V. Shimanov ◽

Roman V. Deitch ◽

...

Keyword(s):

Treatment Efficacy ◽

Gene Polymorphisms ◽

Haplotype Analysis ◽

Drug Effects ◽

Efficacy And Safety ◽

Adverse Drug Effects ◽

Extensive Metabolisers ◽

Intermediate Metabolism ◽

Brief Psychotic Disorder ◽

Icd 10

Abstract Objectives To identify possible associations of CYP2D6, CYP3A4/5, and ABCB1 gene polymorphisms with the efficacy and safety of antipsychotics in adolescents with acute psychotic episodes. Methods We examined the associations of pharmacogenetic factors with the efficacy and safety of antipsychotics in 101 adolescents with acute psychotic episodes. The diagnosis on admission was “Brief psychotic disorder” (F23.0–23.9 by ICD-10). All patients were administered antipsychotics for 14 days. Treatment efficacy and safety were assessed using the PANSS, CGAS, CGI-S(I), UKU SERS, BARS, and SAS scales. Pharmacokinetic genotyping was performed for the CYP2D6*4, *10, ABCB1 1236C>T, 2677G>T, and 3435C>T genes. Results CYP2D6 intermediate metabolisers had “Micturition disturbances” more often than extensive metabolisers (24.2 vs. 7.4%; p=0.026). “Wild” homozygote ABCB1 3435C>T CC was associated with more prominent akathisia. Haplotype analysis of three ABCB1 polymorphisms revealed that the “wild” alleles “C-G-C” (ABCB1 1236-2677-3435) were associated with higher risk of “Reduced salivation” (OR=2.95; 95% CI=1.35–6.45; p=0.0078). Conclusions CYP2D6 intermediate metabolism was associated with the risk of urinary difficulties under treatment with antipsychotics. We found that “wild” homozygotes ABCB1 1236C>T, 2677G>T, and 3435C>T were predictors of adverse drug effects caused by treatment with antipsychotics.

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