Identification of human UGT isoforms responsible for glucuronidation of efavirenz and its three hydroxy metabolites

Abstract

1. Uridine 5′-diphosphate-glucuronosyltransferases (UGTs) involved in the glucuronide formation of efavirenz (EFV) and its three hydroxy metabolites, 8-hydroxyefavirenz (8-OH EFV), 7-hydroxyefavirenz (7-OH EFV), and 8,14-dihydroxyefavirenz (8,14-diOH EFV), were assessed.

2. Among 12 recombinant UGT isoforms tested, only UGT2B7 showed catalytic activity in the formation of EFV-N-glucuronide (EFV-G) as previously reported. On the other hand, almost all UGT isoforms were involved in the glucuronidation of the three hydroxy metabolites, although their relative contribution is unclear.

3. The catalytic activities in the formation of EFV-G by 17 different human liver microsomes exhibit a more than 40-fold inter-individual variability, whereas those of glucuronidation of the three hydroxy metabolites showed almost identical activity.

4. The formation of EFV-G showed a significant correlation (r = 0.920; p < 0.0001) with UGT2B7-catalysed azidothymidine glucuronidation in 17 different human liver microsomes. Furthermore, fluconazole, a known UGT2B7 inhibitor, potently inhibited the formation of EFV-G up to 80%. This suggests that EFV might be a specific UGT2B7 substrate in vitro.

5. This is the first study identifying specific UGT isozymes that glucuronidate EFV and its three hydroxy metabolites. Continued identification and characterisation of these pathways may help reduce adverse effects such as CNS toxicity in EFV therapy.

Keywords::

• Efavirenz
• 7-hydroxyefavirenz
• 8-hydroxyefavirenz
• 8,14-dihydroxyefavirenz
• glucuronidation
• UGTs

Acknowledgements

The authors would like to acknowledge contributions of graduate students at PharmacoGenomics Research Center, Inje University College of Medicine in this research including Hunmi Kim, Fen Jiang, and Kyeong-Seok Oh.

Declaration of interest

This study was supported by the grant from Inje University, 2008 and The Catholic University of Korea, 2011. A portion of the information in this manuscript has been presented previously: Soo Kyung Bae, Hyunmi Kim, Kyung-Seok Oh, Fen Jinag, Hoon Cho, Ji-Hong Shon, Jae-Gook Shin. 2010. In vitro glucuronidation of EFV and its hydroxy metabolites in human liver microsomes, 111th Annual Meeting of the American Society for Clinical Pharmacology and Therapeutics, Atlanta, GA, USA.