Venkatakrishnan K, von Moltke L L, Greenblatt D J
Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, Boston, Massachusetts 02111, USA.
Clin Pharmacokinet. 2000 Feb;38(2):111-80. doi: 10.2165/00003088-200038020-00002.
This article reviews the metabolic pharmacokinetic drug-drug interactions with the systemic antifungal agents: the azoles ketoconazole, miconazole, itraconazole and fluconazole, the allylamine terbinafine and the sulfonamide sulfamethoxazole. The majority of these interactions are metabolic and are caused by inhibition of cytochrome P450 (CYP)-mediated hepatic and/or small intestinal metabolism of coadministered drugs. Human liver microsomal studies in vitro, clinical case reports and controlled pharmacokinetic interaction studies in patients or healthy volunteers are reviewed. A brief overview of the CYP system and the contrasting effects of the antifungal agents on the different human drug-metabolising CYP isoforms is followed by discussion of the role of P-glycoprotein in presystemic extraction and the modulation of its function by the antifungal agents. Methods used for in vitro drug interaction studies and in vitro-in vivo scaling are then discussed, with specific emphasis on the azole antifungals. Ketoconazole and itraconazole are potent inhibitors of the major drug-metabolising CYP isoform in humans, CYP3A4. Coadministration of these drugs with CYP3A substrates such as cyclosporin, tacrolimus, alprazolam, triazolam, midazolam, nifedipine, felodipine, simvastatin, lovastatin, vincristine, terfenadine or astemizole can result in clinically significant drug interactions, some of which can be life-threatening. The interactions of ketoconazole with cyclosporin and tacrolimus have been applied for therapeutic purposes to allow a lower dosage and cost of the immunosuppressant and a reduced risk of fungal infections. The potency of fluconazole as a CYP3A4 inhibitor is much lower. Thus, clinical interactions of CYP3A substrates with this azole derivative are of lesser magnitude, and are generally observed only with fluconazole dosages of > or =200 mg/day. Fluconazole, miconazole and sulfamethoxazole are potent inhibitors of CYP2C9. Coadministration of phenytoin, warfarin, sulfamethoxazole and losartan with fluconazole results in clinically significant drug interactions. Fluconazole is a potent inhibitor of CYP2C19 in vitro, although the clinical significance of this has not been investigated. No clinically significant drug interactions have been predicted or documented between the azoles and drugs that are primarily metabolised by CYP1A2, 2D6 or 2E1. Terbinafine is a potent inhibitor of CYP2D6 and may cause clinically significant interactions with coadministered substrates of this isoform, such as nortriptyline, desipramine, perphenazine, metoprolol, encainide and propafenone. On the basis of the existing in vitro and in vivo data, drug interactions of terbinafine with substrates of other CYP isoforms are unlikely.
唑类药物酮康唑、咪康唑、伊曲康唑和氟康唑，烯丙胺类药物特比萘芬以及磺胺类药物磺胺甲恶唑。这些相互作用大多是代谢性的，是由细胞色素P450（CYP）介导的肝和/或小肠对同时服用药物的代谢抑制所致。本文回顾了体外人肝微粒体研究、临床病例报告以及患者或健康志愿者的对照药代动力学相互作用研究。在简要概述CYP系统以及抗真菌药物对不同人类药物代谢CYP同工型的不同作用之后，讨论了P-糖蛋白在前体系统提取中的作用以及抗真菌药物对其功能的调节。然后讨论了用于体外药物相互作用研究和体外-体内标度的方法，特别强调了唑类抗真菌药物。酮康唑和伊曲康唑是人类主要药物代谢CYP同工型CYP3A4的强效抑制剂。这些药物与CYP3A底物如环孢素、他克莫司、阿普唑仑、三唑仑、咪达唑仑、硝苯地平、非洛地平、辛伐他汀、洛伐他汀、长春新碱、特非那定或阿司咪唑同时给药可导致具有临床意义的药物相互作用，其中一些可能危及生命。酮康唑与环孢素和他克莫司的相互作用已被用于治疗目的，以降低免疫抑制剂的剂量和成本，并降低真菌感染的风险。氟康唑作为CYP3A4抑制剂的效力要低得多。因此，CYP3A底物与这种唑类衍生物的临床相互作用程度较小，通常仅在氟康唑剂量≥200mg/天时才会观察到。氟康唑、咪康唑和磺胺甲恶唑是CYP2C9的强效抑制剂。苯妥英、华法林、磺胺甲恶唑和氯沙坦与氟康唑同时给药会导致具有临床意义的药物相互作用。氟康唑在体外是CYP2C19的强效抑制剂，尽管其临床意义尚未得到研究。在唑类药物与主要由CYP1A2、2D6或2E1代谢的药物之间，尚未预测或记录到具有临床意义的药物相互作用。特比萘芬是CYP2D6的强效抑制剂，可能与该同工型的同时服用底物如去甲替林、地昔帕明、奋乃静、美托洛尔、恩卡尼和普罗帕酮产生具有临床意义的相互作用。根据现有的体外和体内数据，特比萘芬与其他CYP同工型底物的药物相互作用不太可能发生。
