Effect of ketoconazole and terbinafine on the pharmacokinetics of caffeine in healthy volunteers

Abstract

Summary The effects of single oral doses of ketoconazole 400 mg and terbinafine 500 mg on the hepatic microsomal system have been investigated in 8 healthy male volunteers. Microsomal activity caffeine was assessed by following the metabolism of 3 mg/kg bodyweight i.v. administered 1 h after the drug. The inhibitory effect of terbinafine was more pronounced than that of ketoconazole: clearance was decreased from 1.34 ml·kg⁻¹·min⁻¹ in controls to 1.06 and 1.21 ml·kg⁻¹·min⁻¹, respectively, and the corresponding half-life was increased from 5.8 h in controls to 7.6 and 6.7 h, respectively. The apparent volume of distribution remained unchanged. The serum levels of the antimycotics were within the therapeutic range in each subject. Although all three substances are metabolised by microsomes, the kinetic parameters (C_max, half-life, elimination constant) of the antimycotics were poorly if at all correlated with the elimination of caffeine.