RESUMEN
Tamoxifen is used in clinical practice for breast cancer patients and to prevent osteoporosis. Red clover (Trifolium pratense) preparations are consumed worldwide as dietary supplements for relieving postmenopausal symptoms. In the present study we investigated the possible herb-drug interaction between red clover and tamoxifen in rats. 15 days pre-treatment with red clover did not alter the tamoxifen and its active metabolite 4-hydroxytamoxifen pharmacokinetics significantly (p > 0.05). Therefore the therapeutic efficacy of the tamoxifen may not be compromised by the co-administration with red clover. Tamoxifen metabolism is primarily mediated by CYP2D6, CYP3A4 with minor contribution from CYP2C9, CYP2E1 and CYP1A2 isoforms. Although, red clover pre-treatment significantly (p < 0.05) decreased the mRNA expression and activity of CYP3a2, no effect on CYP2d4 and increased expression and activity of CYP2c11 could be the plausible reasons for lack of effect on tamoxifen and its metabolite pharmacokinetics in rats. CYP1a1 and CYP2b2 mRNA expression and activity were also significantly reduced by red clover. To extend the clinical utility of the present study, effect of red clover extract on major CYPs using human liver microsomes and HepG2 cell lines were also determined. Similar finding were observed in the human liver preparations as in rats.
Asunto(s)
Extractos Vegetales/farmacología , Tamoxifeno/análogos & derivados , Tamoxifeno/farmacocinética , Trifolium/química , Animales , Área Bajo la Curva , Hidrocarburo de Aril Hidroxilasas/genética , Hidrocarburo de Aril Hidroxilasas/metabolismo , Citocromo P-450 CYP1A1/genética , Citocromo P-450 CYP1A1/metabolismo , Citocromo P-450 CYP2D6/genética , Citocromo P-450 CYP2D6/metabolismo , Citocromo P-450 CYP3A/genética , Citocromo P-450 CYP3A/metabolismo , Femenino , Semivida , Células Hep G2 , Humanos , Microsomas Hepáticos/metabolismo , Extractos Vegetales/análisis , Extractos Vegetales/química , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , ARN Mensajero/metabolismo , Curva ROC , Ratas , Ratas Sprague-Dawley , Esteroide Hidroxilasas/genética , Esteroide Hidroxilasas/metabolismo , Tamoxifeno/análisis , Trifolium/metabolismoRESUMEN
AIM: Tamoxifen and centchroman are two non-steroidal, selective estrogen receptors modulators, intended for long term therapy in the woman. Because of their wide spread use, there is a possibility of co-prescription of these agents. MATERIALS & METHODS: We studied the probable pharmacokinetic interaction between these agents in breast cancer model rats. A simple, sensitive and rapid LC-ESI-MS/MS method was developed and validated for the simultaneous determination of tamoxifen, centchroman and their active metabolites. RESULTS: The method was linear over a range of 0.2-200 ng/ml. All validation parameters met the acceptance criteria according to regulatory guidelines. CONCLUSION: LC-MS/MS method for determination of tamoxifen, centchroman and their metabolites was developed and validated. Results show the potential of drug-drug interaction upon co-administration these two marketed drugs.