In vitro inhibitory effects of asiaticoside and madecassoside on human cytochrome P450 |
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| Authors: | T. WinitthanaN. Niwattisaiwong C. PatarapanichM.H. Tantisira S. Lawanprasert |
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| Affiliation: | a Department of Pharmacology and Physiology, Preclinical Efficacy and Safety Assessment Unit, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand
b Department of Food and Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand |
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| Abstract: | The inhibitory effects and types of inhibition of asiaticoside and madecassoside on human CYPs were studied in vitro using recombinant human CYPs. The median inhibitory concentrations (IC50) of asiaticoside and madecassoside were determined for CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4. Asiaticoside inhibited CYP2C19 (IC50 = 412.68 ± 15.44 μM) and CYP3A4 (IC50 = 343.35 ± 29.35 μM). Madecassoside also inhibited CYP2C19 (IC50 = 539.04 ± 14.18 μM) and CYP3A4 (IC50 = 453.32 ± 39.33 μM). Asiaticoside and madecassoside had no effect on the activities of CYP1A2, CYP2C9 and CYP2D6 and CYP2E1. Assessment of mechanism-based inhibition and the type of inhibition were performed for asiaticoside and madecassoside with CYP2C19 and CYP3A4. These results suggested that madecassoside is a mechanism-based inhibitor of CYP2C19 and CYP3A4. Assessment of mechanism-based inhibition by asiaticoside was limited by its low solubility. Asiaticoside exhibited non-competitive inhibition of CYP2C19 (Ki = 385.24 ± 8.75 μM) and CYP3A4 (Ki = 535.93 ± 18.99 μM). Madecassoside also showed non-competitive inhibition of CYP2C19 (Ki = 109.62 ± 6.14 μM) and CYP3A4 (Ki = 456.84 ± 16.43 μM). These results suggest that asiaticoside and madecassoside could cause drug-drug interactions via inhibition of CYP2C19 and CYP3A4. An in vivo study is needed to examine this further. |
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| Keywords: | BOMCC, 7-benzyloxymethyloxy-3-cyanocoumarin CYP, cytochrome P450 DBOMF, dibenzyloxymethylfluorescein EOMCC, ethoxymethyloxy-3-cyanocoumarin IC50, median inhibitory concentration Ki, inhibition constant Km, the Michaelis constant MW, molecular weight NADP+, nicotinamide adenine dinucleotide phosphate NADPH, nicotinamide adenine dinucleotide phosphate (reduced form) SD, standard deviation SE, standard error of the mean Vmax, the maximum velocity of the reaction |
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