Journal
JOURNAL OF PHARMACEUTICAL SCIENCES
Volume 104, Issue 1, Pages 244-256Publisher
WILEY-BLACKWELL
DOI: 10.1002/jps.24250
Keywords
warfarin; UGT; zidovudine; drug-drug interactions; phase II metabolism; pharmacokinetics; bioavailability
Funding
- National Natural Science Foundation of China [81373496]
- Program for Pearl River New Stars of Science and Technology in Guangzhou [2014059]
- Ministry of Education of China [20134401120014]
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In this study, we aimed to determine the modulatory effects of warfarin (an extensively used anticoagulant drug) and its metabolites on UDP-glucuronosyltransferase (UGT) activity and to assess the potential of warfarin to alter the pharmacokinetics of zidovudine (AZT). The effects of warfarin and its metabolites on glucuronidation were determined using human and rat liver microsomes (HLM and RLM) as well as expressed UGTs. The mechanisms of warfarin-UGT interactions were explored through kinetic characterization and modeling. Pharmacokinetic studies with rats were performed to evaluate the potential of warfarin to alter the pharmacokinetics of AZT. We found that warfarin was an effective modifier of a panel of UGT enzymes. The effects of warfarin on glucuronidation were inhibitory for UGT1A1, 2B7, and 2B17, but activating for UGT1A3. Mixed effects were observed for UGT1A7 and 1A9. Consistent with its inhibitory effects on UGT2B7 activity, warfarin inhibited AZT glucuronidation in HLM (K-i = 74.9-96.3 M) and RLM (K-i = 190-230 M). Inhibition of AZT glucuronidation by UGT2B7, HLM, and RLM was also observed with several hydroxylated metabolites of warfarin. Moreover, the systemic exposure (AUC) of AZT in rats was increased by a 1.5- to 2.1-fold upon warfarin coadministration. The elevated AUC was associated with suppressed glucuronidation that was probably attained through a combined action of warfarin and its hydroxylated metabolites. In conclusion, the activities of multiple UGT enzymes can be modulated by warfarin and the nature of modulation was isoform dependent. Also, pharmacokinetic interactions of zidovudine with warfarin were highly possible through inhibition of UGT metabolism. (c) 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 104:244-256, 2015
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