Drug Metabolism

Sildenafil Metabolism

Sildenafil is rapidly absorbed and distributed throughout tissues following oral ingestion. Maximum plasma concentration occurs between 30 minutes to 2 hours following oral administration. Absorption and plasma concentration can be reduced if taken with food.

Following absorption in the gut, sildenafil enters the hepatic vein in high concentration. As sildenafil makes its first pass through the liver, much of it is metabolized by the cytochrome P450 enzyme system. The P450 enzyme system breaks sildenafil into a number of metabolites. One of these metabolites is UK-103,320 which retains some PDE-5 inhibiting capacity. The sildenafil which is not metabolized and the UK-103,320 are then distributed throughout the body having the primary effect of blocking PDE-5 activity in the corpus caverosa. Sildenafil and metabolites are cleared primarily through billiary system with about 80% excreted in feces. The half-life of sildenafil is about 4 hours.

The P450 enzyme responsible for most sildenafil metabolism is CYP3A4. This enzyme is known to be inhibited by a number of substances. Some of the substances which have been demonstrated to interfere with the CYP3A4 metabolism of sildenafil include: ketoconazole, erythromycin, cimetidine and ritonavir. Inhibiting the action of CYP3A4 results in increased plasma sildenafil concentration and an extended half-life.

Grapefruit is a known intestinal CYP3A4 inhibitor. Research indicates that grapefruit can increase the bioavailablity of sildenafil. While the effects are modest it may be wise to avoid concominant use.

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The presence of food in the gut can effect the absorption and plasma concentration of sildenafil .