Effects of the Antifungal Agents on Oxidative Drug Metabolism

Abstract

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.

Lack of effect of ketoconazole on the pharmacokinetics of rosuvastatin in healthy subjects

“…Ketoconazole is known to have inhibitory effects on the transport protein P-gp [16]. Active-or facilitated-transport processes may have a role in the absorption and disposition of rosuvastatin [17,18].…”

Has the era of individualised medicine arrived for antifungals? A review of antifungal pharmacogenomics

“…43 Fluconazole inhibits, but is not a substrate of, several CYP enzymes (Table 4). It inhibits 2C9, 2C19 and to a lesser extent 3A4, 44,45 but not CYP1A2, 46 2A6 or 2E1. Its ability to inhibit 2C9 and 2C19 causes potential drug interactions particularly relevant to HSCT recipients; for example, the interaction with CY may result in increased formation of toxic metabolites, 47 although others have noted a protective effect of co-administration.…”

“…Fluconazole Potent inhibitor of CYP2C9 and CYP2C19, 44,45 and less so for CYP3A4. 160 No inhibition of P-gp [160][161][162] or BCRP.…”

Pharmacokinetic Drug Interactions with Vandetanib during Coadministration with Rifampicin or Itraconazole

“…[15] On day 4, gmean (CV%) AUC from time 0 to 24 hours (AUC 24 ) and C max of itraconazole were 5042 ng Á h/mL (65.6) and 424.0 ng/mL (55.2), respectively. On day 4, gmean (CV%) AUC 24 and C max of hydroxy-itraconazole were 7688 ng Á h/mL (56.8) and 412.6 ng/mL (40.6), respectively.…”