Comparative human pharmacokinetics and metabolism of single-dose oral and intravenous sildenafil.
OBJECTIVE
To characterize the absorption, metabolism and excretion of an oral and intravenous (IV) dose of radiolabelled [14C]-sildenafil citrate in healthy male subjects. Specific objectives were to measure the cumulative amount of drug-related radiolabelled material excreted in the urine and faeces to characterize urinary and faecal radioactivity as unchanged sildenafil or its metabolites, and to quantify blood and plasma total radioactivity and unchanged drug concentrations.


METHODS
Six healthy male subjects between the ages of 45 and 58 years were enrolled in an open-label, parallel-group study; three subjects received the oral dose and three received the IV dose. Oral drug was administered as a single dose of 50-mg [14C]-sildenafil, and IV drug was administered as a single dose of 25-mg [14C]-sildenafil infused over 25 min. Each dosage form contained 50 microCi of radioactivity. For radioactivity assays, whole blood, plasma, urine and faeces samples were taken predose and at specified intervals up to 5 days postdose. Plasma samples were assayed for sildenafil and the metabolites UK-103,320 and UK-150,564. Metabolite profiling was also performed in plasma, faeces and urine.


RESULTS
Absorption of sildenafil after oral administration was rapid and approximately 92% whilst the absolute bioavailability was limited to 38%, due to first-pass metabolism. Mean AUCt values showed that sildenafil accounted for about 60% of the total circulating radioactivity in the plasma after IV administration and for 32% after oral administration. Concentrations of radioactivity in whole blood were lower than in plasma, indicating limited penetration of sildenafil into blood cells. No unchanged sildenafil was detected in either urine or faeces, demonstrating that metabolism was the major mechanism of drug clearance. The principal routes of metabolism were N-demethylation, oxidation and aliphatic dehydroxylation. Sildenafil was well tolerated, with treatment-related adverse events reported by three subjects. Two of these were mild, and there was one case of moderate leg pain.


CONCLUSIONS
The pharmacokinetics of radiolabelled [14C]-sildenafil were consistent with rapid absorption, first-pass metabolism and primarily faecal elimination of N-demethylated metabolites.
Muirhead
Gary J
GJ
Clinical Sciences, Pfizer Central Research, Sandwich, Kent, UK.
Rance
David J
DJ
Walker
Donald K
DK
Wastall
Philip
P
D000284:Administration, Oral; D000328:Adult; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D004305:Dose-Response Relationship, Drug; D005243:Feces / Q000737:chemistry; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics; D010879:Piperazines / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics; D011687:Purines; D000068677:Sildenafil Citrate; D013450:Sulfones
D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D000068677:Sildenafil Citrate