Aims To determine the absolute bioavailability, dose proportionality and the effects of food on the pharmacokinetics of single oral doses of sildena®l citrate. Methods Three open-label, randomized crossover studies were conducted in healthy male subjects. Absolute bioavailability was determined by comparing pharmacokinetic data after administration of single oral and intravenous 50-mg doses of sildena®l (n=12 subjects). Food effects were examined by comparing pharmacokinetic data for sildena®l and its primary circulating metabolite, UK-103,320, after administration of a single oral 100-mg dose in the fasted and fed states (n=34 subjects). Dose proportionality was assessed from pharmacokinetic data obtained after administration of four single oral doses of sildena®l (25, 50, 100 and 200 mg) to 32 subjects. The safety and tolerability of sildena®l were also assessed in all of these studies. Results The calculated absolute oral bioavailability of sildena®l was 41% (90% CI: 36 ±47). Food slowed the rate of absorption, delaying mean t max by approximately 1 h and reducing C max by 29% (90% CI: 19±38). Systemic exposure, as assessed by the mean area under the plasma concentration±time curve (AUC), was reduced by 11% (90% CI: 6±16). These food effects were not considered to be of clinical signi®cance. There was statistical evidence of nonproportionality in C max and AUC over the dose range 25±200 mg. However the degree of nonproportionality was small, with predicted increases in C max and AUC of 2.2-and 2.1-fold, respectively, for a doubling in dose, and was thought to be clinically nonsigni®cant. Sildena®l was well tolerated in the three studies; the majority of adverse events were mild and transient. Conclusions Sildena®l had a mean absolute bioavailability of 41%. Food caused small reductions in the rate and extent of systemic exposure; these reductions are unlikely to be of clinical signi®cance. Across the dose range of 25±200 mg, systemic exposure increased in a slightly greater than dose-proportional manner.

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The administration of drugs together suggests an inhibition of debrisoquin metabolism caused by the concurrent drugs given. By separating debrisoquin from the other cocktail drugs, this method is likely to be used as a tool to phenotype the enzymes CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 with only 2 urinary collections and 2 blood-sampling occasions.