Association between CYP2C19*17 and metabolism of amitriptyline, citalopram and clomipramine in Dutch hospitalized patients.
Polymorphisms in genes coding for drug metabolizing enzymes, such as the cytochrome P450 enzymes CYP2C19 and CYP2D6, can lead to therapy failure and side effects. In earlier studies, the novel variant CYP2C19*17 increased metabolism of several CYP2C19 substrates. The objective of this study was to evaluate the impact of CYP2C19*17 on the metabolism of amitriptyline (AT), citalopram (CIT), and clomipramine (CLOM). Six-hundred and seventy-eight patients were included in this study, based on availability of DNA and serum levels of parent drug and main metabolite. We investigated the relationship between CYP2C19 genotypes and metabolic parameters, including serum levels corrected for dose and metabolic ratio (MR). The CYP2C19*17 allele was significantly associated with decreased MR for CIT (CYP2C19*1/*17 mean MR=2.3, compared with CYP2C19*1/*1 mean MR=2.8) and AT (CYP2C19*17/*17 mean MR=0.8, compared with CYP2C19*1/*1 mean MR=3.7 in the CYP2D6*1/*1 subgroup). Furthermore, significant association of CYP2D6 genotype with AT, CIT, and CLOM metabolism was observed. No clear correlation was found between CYP2C19 genotype and CLOM metabolism. This study confirms the increased activity of the CYP2C19*17 allele and shows increased metabolism of drugs that are metabolized by CYP2C19, including AT and CIT. However, the clinical relevance of CYP2C19*17 is probably limited for AT, CIT, and CLOM.
Department of Clinical Chemistry, St Jansdal Hospital, Harderwijk, The Netherlands.
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de Vos
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van der Weide
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Loovers
D000293:Adolescent; D000328:Adult; D000368:Aged; D000483:Alleles; D000639:Amitriptyline / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D054316:Biomarkers, Pharmacological; D015283:Citalopram / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D002997:Clomipramine / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D065731:Cytochrome P-450 CYP2C19; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D009426:Netherlands; D011110:Polymorphism, Genetic
D054316:Biomarkers, Pharmacological; D015283:Citalopram; D000639:Amitriptyline; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D019389:Cytochrome P-450 CYP2D6; D002997:Clomipramine