氟康唑与利福平合用

氟康唑说明书：与利福平合用后，其药时曲线下面积减少25%，应增加氟康唑的用量。但增加多少呢？是25%吗？如再与异烟肼合用呢？异烟肼也是药酶抑制剂，如何进行药量增减呢？
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有报道，同时使用利福平可导致氟康唑浓度降低。
利福平也可导致伊曲康唑的血浓度明显降低[6,10~12]。虽然同时使用利福布丁，可导致伊曲康唑浓度降低，但这一联合对治疗隐球菌病有协同作用，但对脂溢性皮炎及球虫病则无协同作用[11]。
同时使用利福平亦可导致氟康唑浓度降低[9,13,14]。
对同时使用利福布丁与氟康唑的272名病人的回顾性分析表明，两药合用后鸟分枝杆菌血症的发病率较两药单独使用降低，而白细胞减少的发病率则较单独使用利福布丁高[15]。
其他咪唑类抗真菌药（如咪康唑、克霉唑、益康唑等）化学结构及药理作用与酮康唑相似，可能与利福平或利福布丁发生类似相互作用，但尚无文献报道。
机制：已知利福平为肝微粒体酶诱导剂，可能促进酮康唑的代谢，从而导致其血浓度降低，作用减弱[1,2]。由于利福平血浓度的降低仅发生于两药同时服用时，间隔12hr则无此影响，故可能是酮康唑影响利福平的吸收所致。
至于利福布丁与氟康唑的相互作用，氟康唑是细胞色素P-450酶系统的有效抑制剂[16]，两药合用时，利福布丁及其代谢物的最大血药浓度及曲线下面积至少增加80%[15]。
建议：两药合用期间，应当监测药物的疗效是否减弱。酮康唑的剂量可能需要增加。错开服药时间（至少间隔12hr）可防止利福平血浓度的降低[1,4,5]。同时使用利福布丁与氟康唑可降低鸟分枝杆菌血症的发病率，但应当权衡白细胞减少的风险[15]。
参考文献：1、Engelhard, D., and others: Interaction of ketoconazole with rifampin and isoniazid, N. Engl. J. Med. 311:1681, 1984.
2、Brass, C., and others: Disposition of ketoconazole, an oral antifungal, in humans, Antimicrob. Agents Chemother. 21:151, 1982.
3、Drouhet, E., and Dupont, B.: Laboratory and clinical assessment of ketoconazole in deep-seated mycoses, Am. J. Med. 74(1B):30, 1983.
4、Abadie-Kemmerly, S., and others: Failure of ketoconazole treatment of Blastomyces dermatidis due to interaction of isoniazid and rifampin (letter), Ann. Intern. Med. 106:844, 1988.
5、Doble, N., and others: Pulmonary Mycobacterium tuberculosis in acquired immune deficiency syndrome, Br. Med. J. 291:849, 1985.
6、Meunier, F.: Serum fungistatic and fungicidal activity in volunteers receiving antifungal agents, Eur. J. Clin. Microbiol. 5:103, 1986.
7、Doble, N., and others: Pharmacokinetic study of the interaction between rifampin and ketoconazole, J. Antimicrob. Chemother. 21:633, 1988.
8、Venkatesan, K.: Pharmacokinetic drug interactions with rifampicin, Clin. Pharmacokinet, 22:47, 1992.
9、Apeloff, G., and others: Induction of fluconazole metabolism by rifampin: in vivo study in humans, J. Clin. Pharmacol. 31:358, 1991.
10、Blomley, M., and others: Itraconazole and anti-tuberculosis drugs (letter), Lancet 336:1255, 1990.
11、Tucker, R.M., and others: Interaction of azoles with rifampin, phenytoin, and carbamazepine: in vitro and clinical observations, Clin. Infect. Dis. 14:165, 1992.
12、Dickinson, G.: Co-administration of rifampin and itraconazole leads to undetectable levels of serum itraconazole, Clin. Infect. Dis. 18:266, 1994.
13、Dupont, B., and Drouhet, E.: Fluconazole in the management of oropharyngeal candidiasis in a predominantly HIV antibody-positive group of patients, J. Med. Vet. mycol. 26:67, 1988.
14、Coker, R.J., anf others: Interaction between fluconazole and rifampicin, Brit. Med. J. 301, 818, 1990.
15、Narang, P.K., and others: Fluconazole and enhanced effect of rifabutin prophylaxis, N. Engl. J. Med. 205:1316, 1994.
16、Bennett, J.E.: Antimicrobial agents: antifungal agents. In: Gilman, A.G., Rall, T.W., Neis, A.S., and Taylor, P. (editors). Goodman and Gilman’s The Pharmacological Basis of Therapeutics. Eighth edition. New York: Pergamon Press. 1990:1165.

异烟肼是CYP2C19的抑制剂和CYP2E1的诱导剂，氟康唑是CYP2C9的抑制剂，利福平是CYP2C8的抑制剂，同时又是CYP2C9和CYP3A4的诱导剂，因此异烟肼不会影响氟康唑的代谢，而利福平会影响。