Effects of the antifungal agents on oxidative drug metabolism - Clinical relevance

This article reviews the metabolic pharmacokinetic drug-drug interactions w ith the systemic antifungal agents: the azoles ketoconazole, miconazole, it raconazole and fluconazole, the allylamine terbinafine and the sulfonamide sul-famethoxazole. The majority of these interactions are metabolic and are caused by inhibition of cytochrome P450 (CYP)-mediated hepatic and/or smal l intestinal metabolism of coadministered drugs. Human liver microsomal studies in vitro, clinical case reports and controll ed pharmacokinetic interaction studies in patients or healthy volunteers ar e reviewed. A brief overview of the CYP system and the contrasting effects of the antifungal agents on the different human drug-metabolising CYP isofo rms is followed by discussion of the role of P-glycoprotein in presystemic extraction and the modulation of its function by the antifungal agents. Met hods used for in vitro drug interaction studies and in vitro-in vivo scalin g an then discussed, with specific emphasis on the azole antifungals. Ketoconazole and itraconazole are potent inhibitors of the major drug-metab olising CYP isoform in humans, CYP3A4. Coadministration of these drugs with CYP3A substrates such as cyclosporin. tacrolimus, alprazolam, triazolam, m idazolam, nifedipine, felodipine, simvastatin, lovastatin, vincristine, ter fenadine or astemizole can result in clinically significant drug interactio ns, 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 ri sk of fungal infections. The potency of fluconazole as a CYP3A4 inhibitor i s much lower. Thus, clinical interactions of CYP3A substrates with this azo le derivative are of leaser magnitude, and are generally observed only with fluconozole dosages of greater than or equal to 200 mg/day. Fluconazole, miconazole and sulfamethoxazole are potent inhibitors of CYP2C 9. Coadministration of phenytoin, warfarin, sulfamethoxazole and losartan w ith fluconazole results in clinically significant drug interactions. Flucon azole is a potent inhibitor of CYP2C19 in vitro, although the clinical sign ificance 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 CYP 1A2, 2D6 or 2E1. Terbinafine is a potent inhibitor of CYP2D6 and may cause clinically signif icant interactions with coadministered substrates of this isoform, such as nortrip-tyline, desipramine, perphenazine. metoprolol, encainide and propaf enone. On the basis of the existing in vitro and in vivo data, drug interac tions of terbinafine with substrates of other CYP isoforms are unlikely.