In vitro evidence for endocrine-disrupting chemical (EDC)'s inhibition of drug metabolism.

BACKGROUND: Humans can be frequently exposed to Bisphenol A (BPA) via multiple sources, and babies are considered to be the most sensitive group to exposure of BPA. AIMS: To investigate the inhibition potential of BPA towards human liver microsomes (HLMs)-catalyzed zidovudine (AZT) glucuronidation. MATERIALS AND METHODS: In vitro HLMs incubation system was used to investigate the inhibition potential of BPA towards AZT glucuronidation. Both Dixon and Lineweaver-Burk plots were employed to determine the inhibition kinetic type, and nonlinear repression was utilized to calculate the inhibition kinetic parameters (Ki). RESULTS: Concentration-dependent inhibition of BPA towards AZT glucuronidation was observed. Both Dixon and Lineweaver-Burk plots showed that BPA exerted competitive inhibition towards the glucuronidation of AZT, and nonlinear repression with competitive equation was used to calculate the Ki value to be 3.2 µM. CONCLUSION: Potential BPA-AZT interaction might occur when the patients administered with AZT is also exposed to BPA.

Acitretin exhibits inhibitory effects towards UDP-glucuronosyltransferase (UGT)1A9-mediated 4-methylumbelliferone (4-MU) and propofol glucuronidation reaction.

The present study aimed to evaluate the potential risk of drug-drug interactions associated with acitretin which is a drug for therapy of psoriasis approved by the Food and Drug Administration (FDA). The initial screening of acitretin's inhibition towards 4-methylumbelliferone (4-MU) glucuronidation catalyzed by important UDP-glucuronosyltransferase (UGT) isoforms in the liver showed that UGT1A9 activity was strongly inhibited by acitretin with other UGT isoforms negligibly influenced. The inhibition type is best fit to competitive inhibition, and the inhibition kinetic parameter (K(i)) was determined to be 3.5 microM. The inhibition behaviour of acitretin towards UGT1A9 activity did not exhibit probe substrate-dependent behaviour when selecting human liver microsomes (HLMs)-catalyzed propofol-O-glucuronidation as probe reaction of UGT1A9. The same inhibition type and similar inhibition parameters (K(i) = 3.2 microM) were obtained. Using the maximum plasma exposure dose of acitretin (C(max)), the C(max)/K(i) values were calculated to be 0.23 and 0.25 when selecting 4-MU and propofol as probe substrates, respectively. All these results indicate a potential clinical drug-drug interaction between acitretin and 4-MU or propofol.