Sildenafil metabolism and clearance

Here is a follow-up on sildenafil – after a question in class. Some of this will make perfect sense to you after the coming drug metabolism lecture.

Firstly, I just discovered that the drug now has a third medical indication. I will have to check whether this indication is officially sanctioned by the FDA, but the drug apparently is useful for the prevention and treatment of high-altitude pulmonary edema associated with altitude sickness such as that suffered by mountain climbers. While this effect has only recently been discovered, sildenafil is already becoming an accepted treatment for this condition, in particular in situations where the standard treatment of rapid descent has been delayed for some reason. I recently read some blogs about climbing Everest (an 80-year old died when trying to set an age record!), but in none of the altitude sickness cases the drug was mentioned.

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 cavernosum. Sildenafil and metabolites are cleared primarily through the biliary 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 bioavailability of sildenafil. While the effects are modest it may be wise to avoid concomitant use.

Protease inhibitors used in treatment of AIDS also are metabolized by the above CYP enzyme(s) and thus also give rise to higher plasma levels of sildenafil based on competition. I am sure that there may be issues sometimes also regarding drugs like warfarin used for blood coagulation control.

(NB: Some of the above was copied straight from the source such as Wikipedia.)