Merck & Co., Inc., Kenilworth, New Jersey, USA.
Merck & Co., Inc., Kenilworth, New Jersey, USA
Antimicrob Agents Chemother. 2019 Mar 27;63(4). doi: 10.1128/AAC.02492-18. Print 2019 Apr.
Doravirine is a novel nonnucleoside reverse transcriptase inhibitor for the treatment of human immunodeficiency virus type 1 infection. studies were conducted to assess the potential for drug interactions with doravirine via major drug-metabolizing enzymes and transporters. Kinetic studies confirmed that cytochrome P450 3A (CYP3A) plays a major role in the metabolism of doravirine, with ∼20-fold-higher catalytic efficiency for CYP3A4 versus CYP3A5. Doravirine was not a substrate of breast cancer resistance protein (BCRP) and likely not a substrate of organic anion transporting polypeptide 1B1 (OATP1B1) or OATP1B3. Doravirine was not a reversible inhibitor of major CYP enzymes (CYP1A2, -2B6, -2C8, -2C9, -2C19, -2D6, and -3A4) or of UGT1A1, nor was it a time-dependent inhibitor of CYP3A4. No induction of CYP1A2 or -2B6 was observed in cultured human hepatocytes; small increases in CYP3A4 mRNA (≤20%) were reported at doravirine concentrations of ≥10 μM but with no corresponding increase in enzyme activity. transport studies indicated a low potential for interactions with substrates of BCRP, P-glycoprotein, OATP1B1 and OATP1B3, the bile salt extrusion pump (BSEP), organic anion transporter 1 (OAT1) and OAT3, organic cation transporter 2 (OCT2), and multidrug and toxin extrusion 1 (MATE1) and MATE2K proteins. In summary, these findings indicate that CYP3A4 and CYP3A5 mediate the metabolism of doravirine, although with different catalytic efficiencies. Clinical trials reported elsewhere confirm that doravirine is subject to drug-drug interactions (DDIs) via CYP3A inhibitors and inducers, but they support the notion that DDIs (either direction) are unlikely via other major drug-metabolizing enzymes and transporters.
多伟拉韦是一种新型非核苷类逆转录酶抑制剂，用于治疗人类免疫缺陷病毒 1 型感染。进行了研究以评估多伟拉韦通过主要药物代谢酶和转运体发生药物相互作用的潜力。动力学研究证实细胞色素 P450 3A（CYP3A）在多伟拉韦的代谢中起主要作用，CYP3A4 对 CYP3A5 的催化效率高约 20 倍。多伟拉韦不是乳腺癌耐药蛋白（BCRP）的底物，可能不是有机阴离子转运多肽 1B1（OATP1B1）或 OATP1B3 的底物。多伟拉韦不是主要 CYP 酶（CYP1A2、-2B6、-2C8、-2C9、-2C19、-2D6 和 -3A4）或 UGT1A1 的可逆抑制剂，也不是 CYP3A4 的时间依赖性抑制剂。在培养的人肝细胞中未观察到 CYP1A2 或 -2B6 的诱导；在多伟拉韦浓度≥10μM 时，报告 CYP3A4 mRNA 仅小幅度增加（≤20%），但酶活性没有相应增加。转运研究表明，与 BCRP、P-糖蛋白、OATP1B1 和 OATP1B3、胆汁盐外排泵（BSEP）、有机阴离子转运蛋白 1（OAT1）和 OAT3、有机阳离子转运蛋白 2（OCT2）以及多药和毒素外排 1（MATE1）和 MATE2K 蛋白的底物发生相互作用的潜力较低。总之，这些发现表明 CYP3A4 和 CYP3A5 介导多伟拉韦的代谢，尽管催化效率不同。其他地方报告的临床试验证实，多伟拉韦易受通过 CYP3A 抑制剂和诱导剂发生的药物相互作用（DDI）的影响，但它们支持这样的观点，即（任何方向的）DDI 不太可能通过其他主要药物代谢酶和转运体发生。
