Beijing Key Laboratory of Drug Resistance Tuberculosis Research, Beijing Tuberculosis and Thoracic Tumor Research Institute, and Beijing Chest Hospital, Capital Medical University, Beijing, China.
Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Antimicrob Agents Chemother. 2017 Dec 21;62(1). doi: 10.1128/AAC.01692-17. Print 2018 Jan.
Drug efflux pumps play important roles in intrinsic and acquired drug resistance. Verapamil, an efflux inhibitor that enhances the activity of bedaquiline, clofazimine, and other drugs against , has been proposed as a potential adjunctive agent for treatment of tuberculosis (TB). However, the extent to which verapamil enhances efficacy by inhibiting bacterial efflux pumps versus inhibiting mammalian drug transporters to improve oral bioavailability has not been delineated. We found that verapamil potentiated the activity of bedaquiline and clofazimine against clinical isolates, including those harboring mutations. Verapamil increased the efficacy of bedaquiline in a murine TB model by the same extent to which it increased systemic bedaquiline exposure. However, verapamil showed no effect on the oral bioavailability or efficacy of clofazimine in mice. The addition of verapamil increased the sterilizing activity of a regimen composed of bedaquiline, clofazimine, and pyrazinamide. These results confirm that verapamil has adjunctive activity , but they also demonstrate that the adjunctive effect is likely due to enhanced systemic exposure to companion drugs via effects on mammalian transporters, rather than inhibition of bacterial pumps. Therefore, there may be no advantage to administering verapamil versus increasing the doses of companion drugs.
药物外排泵在固有和获得性药物耐药性中发挥重要作用。维拉帕米是一种外排抑制剂，可增强乙胺丁醇、氯法齐明和其他药物对的活性，已被提议作为治疗结核病 (TB) 的潜在辅助药物。然而，维拉帕米通过抑制细菌外排泵增强的功效与抑制哺乳动物药物转运体以提高口服生物利用度的程度尚未确定。我们发现维拉帕米增强了乙胺丁醇和氯法齐明对临床分离株的活性，包括那些携带突变的分离株。维拉帕米通过增加系统乙胺丁醇暴露的程度，增强了在小鼠结核病模型中乙胺丁醇的疗效。然而，维拉帕米对小鼠氯法齐明的口服生物利用度或疗效没有影响。添加维拉帕米增加了由乙胺丁醇、氯法齐明和吡嗪酰胺组成的方案的杀菌活性。这些结果证实了维拉帕米具有辅助作用，但也表明辅助作用可能是由于通过对哺乳动物转运体的影响增强了伴随药物的全身暴露，而不是抑制细菌泵。因此，与增加伴随药物的剂量相比，给予维拉帕米可能没有优势。
