Bélanger Anne-Sophie, Caron Patrick, Harvey Mario, Zimmerman Peter A, Mehlotra Rajeev K, Guillemette Chantal
Pharmacogenomics Laboratory, Centre Hospitalier Universitaire de Québec Research Center and Faculty of Pharmacy, Laval University, Québec, Canada.
Drug Metab Dispos. 2009 Sep;37(9):1793-6. doi: 10.1124/dmd.109.027706. Epub 2009 Jun 1.
The non-nucleoside reverse transcriptase inhibitor efavirenz (EFV) is directly conjugated by the UDP-glucuronosyltransferase (UGT) pathway to form EFV-N-glucuronide (EFV-G), but the enzyme(s) involved has not yet been identified. The glucuronidation of EFV was screened with UGT1A and UGT2B enzymes expressed in a heterologous system, and UGT2B7 was shown to be the only reactive enzyme. The apparent K(m) value of UGT2B7 (21 microM) is similar to the value observed for human liver microsomes (24 microM), whereas the variant allozyme UGT2B7*2 (Tyr(268)) displayed similar kinetic parameters. Because 3'-azido-3'-deoxythymidine (AZT), one of the most current nucleotide reverse transcriptase inhibitors prescribed in combination with EFV, is also conjugated by UGT2B7, the potential metabolic interaction between EFV and AZT has been studied using human liver microsomes. Glucuronidation of both drugs was inhibited by one another, in a concentration-dependent manner. At K(m) values (25 and 1000 microM for EFV and AZT, respectively), EFV inhibited AZT glucuronidation by 47%, whereas AZT inhibited EFV glucuronidation by 23%. With a K(i) value of 17 microM for AZT-glucuronide formation, EFV appears to be one of the most selective and potent competitive inhibitor of AZT glucuronidation in vitro. Moreover, assuming that concentrations of EFV achieved in plasma (C(max) = 12.9 microM) are in a range similar to its K(i) value, it was estimated that EFV could produce a theoretical 43% inhibition of AZT glucuronidation in vivo. We conclude that UGT2B7 has a major role in EFV glucuronidation and that EFV could potentially interfere with the hepatic glucuronidation of AZT.
非核苷类逆转录酶抑制剂依非韦伦（EFV）通过尿苷二磷酸葡萄糖醛酸基转移酶（UGT）途径直接结合形成依非韦伦 - N - 葡萄糖醛酸苷（EFV - G），但具体涉及的酶尚未明确。利用在异源系统中表达的UGT1A和UGT2B酶对EFV的葡萄糖醛酸化进行筛选，结果显示UGT2B7是唯一具有活性的酶。UGT2B7的表观米氏常数（K(m)）值（21微摩尔）与人肝微粒体观察到的值（24微摩尔）相似，而变体同工酶UGT2B7*2（Tyr(268)）表现出相似的动力学参数。由于3'-叠氮 - 3'-脱氧胸苷（AZT）是目前与EFV联合使用的最常用的核苷酸逆转录酶抑制剂之一，且它同样由UGT2B7结合，因此已使用人肝微粒体研究了EFV与AZT之间潜在的代谢相互作用。两种药物的葡萄糖醛酸化相互抑制，呈浓度依赖性。在米氏常数（EFV和AZT分别为25和1000微摩尔）下，EFV抑制AZT葡萄糖醛酸化47%，而AZT抑制EFV葡萄糖醛酸化23%。对于AZT - 葡萄糖醛酸苷形成，EFV的抑制常数（K(i)）值为17微摩尔，在体外它似乎是AZT葡萄糖醛酸化最具选择性和效力的竞争性抑制剂之一。此外，假设血浆中达到的EFV浓度（C(max)=12.9微摩尔）与其K(i)值处于相似范围，据估计EFV在体内理论上可产生43%的AZT葡萄糖醛酸化抑制作用。我们得出结论，UGT2B7在EFV葡萄糖醛酸化中起主要作用，且EFV可能潜在干扰AZT的肝脏葡萄糖醛酸化。
