Effects Of Components In The Commonly Used Traditional Chinese Medicines On The Activity Of Cytochrome P450 3A4

The impact of one drug on the efficacy and/or toxicity of another, commonly referred to as a drug-drug interaction, has presented a special challenge in managing patients'health care around the world. This is a result of the exponential increase in adversities with the use of multiple drugs, which is particularly prevalent in AIDS and cancer patients as well as the elderly population. There is a growing awareness that herbal remedies and other phytochemicals, among others, could severely affect the metabolism of conventional prescription drugs, and are emerging as important issues to consider in the evaluation of new drug candidates.Human cytochrome P450 3A4 (CYP3A4) is the single most important drug-metabolizing enzyme. It accounts for roughly 40% of the total cytochrome P450 in human liver microsomes and metabolizes more than 50% of the clinically used drugs. CYP3A4 is the target for a number of drug-drug interactions of significant clinical concern, well-known examples are the induction of CYP3A4 by St. John's wort rendering antiviral treatment less efficient, and the inhibition of the same CYP enzyme by grapefruit juice. The knowledge of drug-drug interactions associated to this enzyme is of interestingly importance during multidrug treatments.In present study, in vitro experiments using recombinant CYP3A4 were carried out to predict potential drug-drug interaction involving the enzyme prior to studies in vivo. Two hundred and twenty-six active components extracted from commonly used traditional Chinese medicines (TCM) were investigated, and 12 of them showed modest to potent inhibition with IC50 values ranged from 4.61 to 14.52μM. To further examined their impacts on the metabolism of CYP3A4, two (bufalin and glycyrrhetinic acid) among the 12 compounds were orally dosed to rats along with midazolam as a probe, and both exhibited alteration of the pharmacokinetic parameters of midazolam as well as inhibitory effect on the formation of 1- hydroxyl midazolam, which implied that additional attention should be paid when bufalin and glycyrrhetinic acid are administered concomitantly with many clinical drugs.