No effect on pharmacokinetics of tamoxifen and 4-hydroxytamoxifen by multiple doses of red clover capsule in rats.

Kanumuri Siva Rama Raju,Muhammad Wahajuddin,Isha Taneja,Jiaur Rahman Gayen,Sheelendra Pratap Singh,Anees Ahmed Syed,Guru Raghavendra Valicherla,Mamunur Rashid,Murali Krishna Challagundla

doi:10.1038/srep16126

Abstract

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.

Highlights

Tamoxifen is used in clinical practice for breast cancer patients and to prevent osteoporosis
Previous reports show that the major metabolites obtained in human liver microsomes resemble qualitatively with that obtained in rat liver microsomes[31,32]
We studied the effect of marketed red clover preparation on the major CYP enzymes responsible for metabolism of tamoxifen in terms of both expression at mRNA level and microsomal activity after the chronic treatment for 15 days in rats to explore the possible reasons that could explain the conceivable interactions

Summary

Introduction

Tamoxifen is used in clinical practice for breast cancer patients and to prevent osteoporosis. 1B1, 1A6, SULTs, UGTs and transporters affecting the bioavailability of tamoxifen, theophylline, oestradiol, DHEA, 4-methyl umbelliferone, nicotine, paclitaxel, daunomycin, vinblastine, mitoxantrone and nitrofurantoin[5,10,11,12,13,14,15,16,17,18,19,20,21,22] All these studies have been conducted with the individual pure constituents and may not represent the true outcome of the red clover consumption as such, which contains mixture of several isoflavonoids that could have synergistic or antagonistic properties when given together. We studied the effect of marketed red clover preparation on the major CYP enzymes responsible for metabolism of tamoxifen in terms of both expression at mRNA level and microsomal activity after the chronic treatment for 15 days in rats to explore the possible reasons that could explain the conceivable interactions. We determined the effect of red clover extract on the activity of CYPs in human liver microsomes and possible induction in HepG2 cells upon 3-day treatment

Methods

Results

Discussion

Conclusion