Inhibition of Human Cytochrome P450 2c8-catalyzed Amodiaquine N-desethylation: Effect of Five Traditionally and Commonly Used Herbs

BACKGROUND: In Southeast Asia and many parts of the world, herbal products are increasingly used in parallel with modern medicine. OBJECTIVE: This study aimed to investigate the effects of herbs commonly used in Southeast Asia on activity of cytochrome P450 2C8 (CYP2C8), an important human hepatic enzyme in drug metabolism. MATERIALS AND METHODS: The selected herbs, such as Eurycoma longifolia Jack (ELJ), Labisia pumila (LP), Echinacea purpurea (EP), Andrographis paniculata (AP), and Ginkgo biloba (GB), were subjected to inhibition studies using an in vitro CYP2C8 activity marker, amodiaquine N-desethylase assay. Inhibition parameters, inhibitory concentration 50% (IC(50)), and K(i) values were determined to study the potency and mode of inhibition. RESULTS: All herbs inhibited CYP2C8 with the following order of potency: LP > ELJ > GB > AP > EP. LP and ELJ inhibited potently at K(i)'s of 2 and 4 times the K(i) of quercetin, the positive control. The inhibition by LP was uncompetitive in nature as compared to competitive or mixed type inhibition observed with other herbs. GB exhibited moderate inhibitory effect at a K(i)6 times larger than quercetin K(i). AP and EP, on the other hand, showed only weak inhibition. CONCLUSION: The herbs we chose represented the more commonly used herbs in Southeast Asia where collision of tradition and modernization in healthcare, if not properly managed, may lead to therapeutic misadventures. We conclude that concurrent consumption of some herbs, in particular, LP and ELJ, may have relevance in drug-herb interactions via CYP2C8 inhibition in vivo. SUMMARY: Herbs are increasingly used in parallel with modern medicines nowadays. In this study five commonly used herbs in Southeast Asia region, ELJ, LP, EP, AP and GB, were investigated for their in vitro inhibitory potency on CYP2C8, an important drug-metaboliz-ing human hepatic enzyme. All herbs inhibited CYP2C8 activity marker, amodiaquine N-desethylation, with potency order of LP > ELJ > GB >AP > EP. LP, ELJ and GB exhibited K(i) values of 2, 4 and 6 times the K(i) of quercetin, the positive control, indicating potent to moderate degree of enzyme inhibition. AP and EP, on the other hand, showed only weak inhibition. In summary, concurrent consumption of some herbs especially LP and ELJ may have relevance in drug-herb interactions via CYP2C8 inhibition in vivo. [Image: see text] Abbreviations Used: AQ: Amodiaquine, AP: Andrographis paniculata, CYP: Cytochrome P450, DEAQ: Desethylamodiaquine, EP: Echinacea purpurea, ELJ: Eurycoma longifolia Jack, GB: Ginkgo biloba, K(i): Inhibition constant, LP: Labisia pumila, Vmax: Maximal velocity, K(m): Michaelis-Menten constant.