Dose‐Dependent Inhibition of the CYP2D6 Catalyzed Oxidation of Sparteine by Mepyramine in Healthy Volunteers

Kortunay, Selim; Bozkurt, Atilla; Başcı, Nursabah E.; Brøsen, Kim; Kayaalp, S. O.

doi:10.1034/j.1600-0773.2001.d01-170.x

Cited by 3 publications

(2 citation statements)

References 12 publications

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“…For this reason similar studies using other CYP2D6 subtrates are needed. In our recent study, we investigated in healthy volunteers the effects of four antihistaminic drugs, mepyramine, clernastine, chlorpheniramine and cetrizine on CYP2D6 activity in single-dose experiments (11). Among the four antihistaminics investigated, only mepyramine inhibited CYP2D6 catalyzed oxidation of sparteine.…”

Section: Discussionmentioning

confidence: 99%

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Effects of terfenadine and diphenhydramine on the CYP2D6 activity in healthy volunteers

Kortunay

Bozkurt

Başcı

et al. 2002

Eur. J. Drug Metab. Pharmacokinet.

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The aim of this study was to investigate the effects of two antihistaminic drugs, terfenadine and diphenhydramine on CYP2D6 activity by using debrisoquine as a model substrate. The study was carried out as an in vivo single-dose study in 12 young, healthy men. All volunteers had previously been identified as debrisoquine-extensive metabolizers. The volunteers took increasing single oral doses of one of the two antihistaminic drugs in randomized order, at weekly intervals, followed 1 h later by debrisoquine test. Terfenadine and diphenhydramine were given in the doses of 60 and 120 mg; 100 and 150 mg, respectively. The 8-hr urinary concentrations of debrisoquine and 4-hydroxydebrisoquine were determined by high-performance liquid chromatography (HPLC). With increasing doses of terfenadine and diphenhydramine, there was no statistically significant increase in the debrisoquine metabolic ratios (P > 0.05, Page's test for trend). The difference between the median debrisoquine metabolic ratios before and after treatments with terfenadine or diphenhydramine were not statistically significant (Wilcoxon's test). This investigation indicates that single-dose administration of diphenhydramine or terfenadine has no effect on the CYP2D6-mediated hydroxylation of debrisoquine in healthy volunteers.

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Section: Discussionmentioning

confidence: 99%

“…Secondly our recent study showed that single-dose mepyramine coadministration resulted in dose-dependent inhibition of the CYP2D6 catalyzed oxidation of sparteine in healthy volunteers (11). However the potential for terfenadine to inhibit the metabolism of other drugs metabolised by CYP2D6, has not been investigated in humans.…”

Section: Methodsmentioning

confidence: 99%

Effects of terfenadine and diphenhydramine on the CYP2D6 activity in healthy volunteers

Kortunay

Bozkurt

Başcı

et al. 2002

Eur. J. Drug Metab. Pharmacokinet.

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Drug-induced changes in P450 enzyme expression at the gene expression level: A new dimension to the analysis of drug–drug interactions

Lee¹,

Ayanoğlu²,

Gong³

2006

Xenobiotica

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Drug-drug interactions (DDIs) caused by direct chemical inhibition of key drug-metabolizing cytochrome P450 enzymes by a co-administered drug have been well documented and well understood. However, many other well-documented DDIs cannot be so readily explained. Recent investigations into drug and other xenobiotic-mediated expression changes of P450 genes have broadened our understanding of drug metabolism and DDI. In order to gain additional information on DDI, we have integrated existing information on drugs that are substrates, inhibitors, or inducers of important drug-metabolizing P450s with new data on drug-mediated expression changes of the same set of cytochrome P450s from a large-scale microarray gene expression database of drug-treated rat tissues. Existing information on substrates and inhibitors has been updated and reorganized into drug-cytochrome P450 matrices in order to facilitate comparative analysis of new information on inducers and suppressors. When examined at the gene expression level, a total of 119 currently marketed drugs from 265 examined were found to be cytochrome P450 inducers, and 83 were found to be suppressors. The value of this new information is illustrated with a more detailed examination of the DDI between PPARalpha agonists and HMG-CoA reductase inhibitors. This paper proposes that the well-documented, but poorly understood, increase in incidence of rhabdomyolysis when a PPARalpha agonist is co-administered with a HMG-CoA reductase inhibitor is at least in part the result of PPARalpha-induced general suppression of drug metabolism enzymes in liver. The authors believe this type of information will provide insights to other poorly understood DDI questions and stimulate further laboratory and clinical investigations on xenobiotic-mediated induction and suppression of drug metabolism.

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Tamoxifen Inhibits Cytochrome P450 2C9 Activity in Breast Cancer Patients

Börüban¹,

Yaşar²,

Babaoğlu³

et al. 2006

Journal of Chemotherapy

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Tamoxifen has been reported to potentiate the anticoagulant effect of warfarin and also to increase the plasma level of phenytoin, which are mainly metabolized by CYP2C9. The aim of this study was to determine the influence of tamoxifen on CYP2C9 activity in vivo in humans. Thirteen breast cancer patients who would start tamoxifen following cytotoxic chemotherapy were enrolled in the study. A single oral dose of 25 mg losartan was given to the patients 2 days before and 2 weeks after starting tamoxifen therapy. Losartan and E3174 in 8-hour urine samples were measured by HPLC. Tamoxifen significantly increased the average urinary losartan/E3174 ratio from 0.73 (CI 95% = 0.15 - 2.30) to 1.66 (CI 95% = 0.68 - 5.20), after 2 weeks of treatment (p = 0.002). Tamoxifen inhibited CYP2C9 activity in breast cancer patients within two weeks of its administration. The inhibition of CYP2C9 activity may be a possible explanation for the drug-drug interaction of tamoxifen with CYP2C9 substrates.

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Dose‐Dependent Inhibition of the CYP2D6 Catalyzed Oxidation of Sparteine by Mepyramine in Healthy Volunteers

Cited by 3 publications

References 12 publications

Effects of terfenadine and diphenhydramine on the CYP2D6 activity in healthy volunteers

Effects of terfenadine and diphenhydramine on the CYP2D6 activity in healthy volunteers

Drug-induced changes in P450 enzyme expression at the gene expression level: A new dimension to the analysis of drug–drug interactions

Tamoxifen Inhibits Cytochrome P450 2C9 Activity in Breast Cancer Patients

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