Polis M A, Piscitelli S C, Vogel S, Witebsky F G, Conville P S, Petty B, Kovacs J A, Davey R T, Walker R E, Falloon J, Metcalf J A, Craft C, Lane H C, Masur H
National Institute of Allergy and Infectious Diseases, National Institute of Health, Bethesda, Maryland 20982-1880, USA.
Antimicrob Agents Chemother. 1997 Aug;41(8):1709-14. doi: 10.1128/AAC.41.8.1709.
The use of antiretroviral agents and drugs for the treatment and prophylaxis of opportunistic infections has lengthened the survival of persons with AIDS. In the era of multidrug therapy, drug interactions are important considerations in designing effective and tolerable regimens. Clarithromycin has had a significant impact on the treatment of disseminated Mycobacterium avium complex infection, and zidovudine is the best-studied and one of the most widely used antiretroviral agents in this population. We conducted a study to determine the maximally tolerated dose of clarithromycin and the pharmacokinetics of clarithromycin and zidovudine individually and in combination. Mixing studies were conducted to simulate potential interaction in the gastric environment. The simultaneous administration of zidovudine and clarithromycin had little impact on the pharmacokinetics of clarithromycin or of its major metabolite. However, coadministration of zidovudine and clarithromycin at three doses (500 mg orally [p.o.] twice daily [b.i.d.], 1,000 mg p.o. b.i.d., and 2,000 mg p.o. b.i.d.) reduced the maximum concentration of zidovudine by 41% (P < 0.005) and the area under the concentration-time curve from 0 to 4 h for zidovudine by 25% (P < 0.05) and increased the time to maximum concentration of zidovudine by 84% (P < 0.05), compared with zidovudine administered alone. Mixing studies did not detect the formation of insoluble complexes due to chelation, suggesting that the decrease in zidovudine concentrations results from some other mechanism. Simultaneous administration of zidovudine and clarithromycin appears to decrease the levels of zidovudine in serum, and it may be advisable that these drugs not be given at the same time. Drug interactions should be carefully evaluated in persons with advanced human immunodeficiency virus infection who are receiving multiple pharmacologic agents.
使用抗逆转录病毒药物以及用于治疗和预防机会性感染的药物延长了艾滋病患者的生存期。在多药治疗时代，药物相互作用是设计有效且耐受性良好的治疗方案时的重要考虑因素。克拉霉素对播散性鸟分枝杆菌复合群感染的治疗产生了重大影响，而齐多夫定是该人群中研究最充分且使用最广泛的抗逆转录病毒药物之一。我们开展了一项研究，以确定克拉霉素的最大耐受剂量以及克拉霉素和齐多夫定单独使用及联合使用时的药代动力学。进行混合研究以模拟胃环境中的潜在相互作用。齐多夫定和克拉霉素同时给药对克拉霉素或其主要代谢产物的药代动力学影响很小。然而，与单独使用齐多夫定相比，同时给予三种剂量（口服500毫克，每日两次；1000毫克，每日两次；2000毫克，每日两次）的齐多夫定和克拉霉素可使齐多夫定的最大浓度降低41%（P<0.005），齐多夫定在0至4小时的浓度-时间曲线下面积降低25%（P<0.05），并使齐多夫定达到最大浓度的时间增加84%（P<0.05）。混合研究未检测到因螯合作用形成不溶性复合物，这表明齐多夫定浓度降低是由其他某种机制导致的。齐多夫定和克拉霉素同时给药似乎会降低血清中齐多夫定的水平，因此这两种药物不同时给药可能是明智的。对于正在接受多种药物治疗的晚期人类免疫缺陷病毒感染患者，应仔细评估药物相互作用。
