The CYP2C19 ultra-rapid metabolizer genotype influences the pharmacokinetics of voriconazole in healthy male volunteers

Wei, Guo; Lei, He-Ping; Li, Zhi; Tan, Zhi‐Rong; Guo, Dong; Li, Fan; Chen, Yao; Hu, Dongli; Wang, Dan; Zhou, Hong‐Hao

doi:10.1007/s00228-008-0574-7

Cited by 153 publications

(134 citation statements)

References 21 publications

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“…17,19,21,22 It was shown that healthy CYP2C19*17/*17 individuals experience a decrease of 52% in systemic omeprazole exposure as compared with healthy wild-type subjects, 21 and it was postulated that *17/*17 individuals would require a 50% increase in escitalopram dose in order to achieve drug exposures similar to *1/*1 subjects. 19 The primary aim of this study was to explore whether the presence of the CYP2C19*17 allele is also correlated with altered imipramine metabolism.…”

Section: Discussionmentioning

confidence: 99%

“…[18][19][20] It is associated with increased gene transcription and thus faster metabolism of CYP2C19 substrates mephenytoin, omeprazole, voriconazole and escitalopram. 17,19,21,22 In contrast to defective CYP2C19*2 and *3 alleles, CYP2C19*17 may thus be associated with ultrarapid metabolism and, therefore, therapeutic failure upon proton pump inhibitor, antifungal or antidepressant treatment. 17,23 The primary aim of this study was to investigate whether the CYP2C19*17 genotype is also correlated with altered imipramine pharmacokinetics.…”

Section: Introductionmentioning

confidence: 99%

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The CYP2C19*17 genotype is associated with lower imipramine plasma concentrations in a large group of depressed patients

et al. 2009

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CYP2C19 converts the tricyclic antidepressant imipramine to its active metabolite desipramine, which is subsequently inactivated by CYP2D6. The novel CYP2C19*17 allele causes ultrarapid metabolism of CYP2C19 substrates. We genotyped 178 depressed patients on imipramine for CYP2C19*17, and measured steady-state imipramine and desipramine plasma concentrations. Mean dose-corrected imipramine plasma concentration was significantly dependent on CYP2C19 genotype (Kruskal-Wallis test, P ¼ 0.01), with circa 30% lower levels in CYP2C19*17/*17 individuals compared with CYP2C19*1/*1 (wild-type) patients. The mean dosecorrected imipramine þ desipramine plasma concentrations and imipramine/desipramine ratios were not significantly different between genotype subgroups (Kruskal-Wallis tests, PX0.12). In a multivariate analysis, we found a significant, but limited effect (P ¼ 0.035, Z 2 ¼ 0.031) of the CYP2C19*17 genotype on imipramine þ desipramine concentrations. Although the CYP2C19*17 allele is associated with a significantly increased metabolism of imipramine, CYP2C19*17 genotyping will, in our view, not importantly contribute to dose management of patients on imipramine therapy guided by imipramine þ desipramine plasma concentrations.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The CYP2C19*17 genotype is associated with lower imipramine plasma concentrations in a large group of depressed patients

et al. 2009

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“…68 A rapid metaboliser 2C19 phenotype has been described, 18 resulting in levels of voriconazole that are significantly lower than either the extensive or poor metaboliser phenotypes. 69 Interestingly, the coexistence of multiple CYP polymorphisms in the same patient do not necessarily have an additive effect on the metabolism of voriconazole. [70][71][72] Metabolism of voriconazole results in several metabolites, the major circulating metabolite being the N-oxide of voriconazole, 65 formed predominantly by CYP3A4 and 2C19, with a smaller contribution from 2C9.…”

Section: Anidulafunginmentioning

confidence: 99%

Has the era of individualised medicine arrived for antifungals? A review of antifungal pharmacogenomics

Ashbee

Gilleece

2011

Bone Marrow Transplant

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“…Sim et al (2006) reported that some nuclear proteins specifically bind to the 5Ј-flanking region of this allele to induce gene transcription. Thus, the heterozygotes (*1/*17) would be ultra-rapid metabolizers (Wang et al, 2009). The frequency of the CYP2C19*17 allele is high (18%) in Ethiopians and Swedes (Sim et al, 2006), 0.64% in Chinese (Wang et al, 2009), and 1.3% in Japanese (Sugimoto et al, 2008).…”

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confidence: 99%

Comparison of Metabolism of Sesamin and Episesamin by Drug-Metabolizing Enzymes in Human Liver

et al. 2012

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ABSTRACT:Sesamin and episesamin are two epimeric lignans that are found in refined sesame oil. Commercially available sesamin supplements contain both sesamin and episesamin at an approximate 1:1 ratio. Our previous study clarified the sequential metabolism of sesamin by cytochrome P450 (P450) and UDP-glucuronosyltransferase in human liver. In addition, we revealed that sesamin caused a mechanism-based inhibition (MBI) of CYP2C9, the P450 enzyme responsible for sesamin monocatecholization. In the present study, we compared the metabolism and the MBI of episesamin with those of sesamin. Episesamin was first metabolized to the two epimers of monocatechol, S-and R-monocatechols in human liver microsomes. The P450 enzymes responsible for S-and R-monocatechol formation were CYP2C9 and CYP1A2, respectively. The contribution of CYP2C9 was much larger than that of CYP1A2 in sesamin metabolism, whereas the contribution of CYP2C9 was almost equal to that of CYP1A2 in episesamin metabolism. Docking of episesamin to the active site of CYP1A2 explained the stereoselectivity in CYP1A2-dependent episesamin monocatecholization. Similar to sesamin, the episesamin S-and R-monocatechols were further metabolized to dicatechol, glucuronide, and methylate metabolites in human liver; however, the contribution of each reaction was significantly different between sesamin and episesamin. The liver microsomes from CYP2C19 ultra-rapid metabolizers showed a significant amount of episesamin dicatechol. In this study, we have revealed significantly different metabolism by P450, UDPglucuronosyltransferase, and catechol-O-methyltransferase for sesamin and episesamin, resulting in different biological effects.

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The CYP2C19 ultra-rapid metabolizer genotype influences the pharmacokinetics of voriconazole in healthy male volunteers

Abstract: Our data indicate that the presence of the CYP2C19*17 allele results in ultra-rapid metabolism of voriconazole after a single oral dose.

Cited by 153 publications

References 21 publications

The CYP2C19*17 genotype is associated with lower imipramine plasma concentrations in a large group of depressed patients

The CYP2C19*17 genotype is associated with lower imipramine plasma concentrations in a large group of depressed patients

Has the era of individualised medicine arrived for antifungals? A review of antifungal pharmacogenomics

Comparison of Metabolism of Sesamin and Episesamin by Drug-Metabolizing Enzymes in Human Liver

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