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

Ming-Lian Yu, Yue Yang, Cong-Min Wang, Meng-Meng Zhang, Miao-Chun Bai, Yue-Ling Guo

Index: Pharmazie 68(6) , 449-52, (2013)

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Abstract

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.