Abstract
The co-use of conventional drug and herbal medicines may lead to herb-drug interaction via modulation of drug-metabolizing enzymes (DMEs) by herbal constituents. UDP-glucuronosyltransferases (UGTs) catalyzing glucuronidation are the major metabolic enzymes of Phase II DMEs. The in vitro inhibitory effect of several herbal constituents on one of the most important UGT isoforms, UGT2B7, in human liver microsomes (HLM) and rat liver microsomes (RLM) was investigated. Zidovudine (ZDV) was used as the probe substrate to determine UGT2B7 activity. The intrinsic clearance (Vmax/Km) of ZDV in HLM is 1.65 µL/mg/min which is ten times greater than in RLM, which is 0.16 µL/mg/min. Andrographolide, kaempferol-3-rutinoside, mitragynine and zerumbone inhibited ZDV glucuronidation in HLM with IC50 values of 6.18 ± 1.27, 18.56 ± 8.62, 8.11 ± 4.48 and 4.57 ± 0.23 µM, respectively, hence, herb-drug interactions are possible if andrographolide, kaempferol-3-rutinoside, mitragynine and zerumbone are taken together with drugs that are highly metabolized by UGT2B7. Meanwhile, only mitragynine and zerumbone inhibited ZDV glucuronidation in RLM with IC50 values of 51.20 ± 5.95 μM and 8.14 ± 2.12 µM, respectively, indicating a difference between the human and rat microsomal model so caution must be exercised when extrapolating inhibitory metabolic data from rats to humans.
Highlights
Drug-metabolizing enzymes can be categorized into two groups which are Phase I and PhaseII enzymes
An high performance liquid chromatography (HPLC) method to quantify zidovudine glucuronide (ZDVG) in liver microsomes was validated in terms of specificity, linearity, sensitivity, precision, accuracy, extraction recovery and matrix effect according to the US Food and Drug Administration (FDA) [41] and International Conference on Harmonisation (ICH) [42]
Prior to the inhibition study, an optimized ZDV incubation assay in human liver microsomes (HLM) and rat liver microsomes (RLM) had been established under a steady state condition where the metabolites formed were not more than 30%
Summary
Drug-metabolizing enzymes can be categorized into two groups which are Phase I and PhaseII enzymes. Drug-metabolizing enzymes can be categorized into two groups which are Phase I and Phase. A compound can be metabolized either during one of the phases or both to be excreted out from the body. Uridine 50 -diphospho-glucuronosyltransferases (UGTs) are the major Phase II metabolizing enzymes responsible for the reaction known as glucuronidation [1]. According to the review by Wells et al [2] in humans approximately 40–70% of clinical drugs are metabolized through this pathway. Endobiotics such as bilirubin, steroids, retinoids and bile acids undergo this route of detoxification [3]
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