Alprostadil

Alprostadil is chemically identical to prostaglandin E₁, the actions of which include vasodilatation of blood vessels in the erectile tissues of the corpora cavernosa and increase in cavernosal artery blood flow, causing penile rigidity.

Alprostadil is present in various mammalian tissues and fluids. It has a diverse pharmacologic profile, among which some of its more important effects are vasodilation, inhibition of platelet aggregation, inhibition of gastric secretion, and stimulation of intestinal and uterine smooth muscle. The pharmacologic effect of alprostadil in the treatment of erectile dysfunction is presumed to be mediated by inhibition of alpha₁-adrenergic activity in penile tissue and by its relaxing effect on cavernosal smooth muscle.

Prostaglandins are potent vasoactive derivatives of arachidonic acid that exert vasomotor, metabolic and cellular effects on the pulmonary and coronary circulation. The E series of prostaglandins produces vasodilation of the systemic and coronary circulation in most species: these prostaglandins have been used for maintaining the patency of the ductus arteriosus in children.

Distribution

Based on studies in several animal species, intravenous or arterially administered prostaglandin E₁ is very rapidly distributed throughout the entire body, with the exception of the central nervous system, where distribution, though detectable, is markedly reduced.

Following intracavernous injection of 20 micrograms of alprostadil, mean peripheral levels of alprostadil at 30 and 60 minutes after injection are not significantly greater than baseline levels of endogenous PGE₁. Peripheral levels of the major circulating metabolite, 15-oxo-13,14-dihydro-PGE₁, increase to reach a peak 30 minutes after injection and return to pre-dose levels by 60 minutes after injection. Any alprostadil entering the systemic circulation from the corpus cavernosum will be rapidly metabolised.

Following intravenous administration, approximately 80% of the circulating alprostadil is metabolised in one pass through the lungs, primarily by beta- and omega-oxidation.

Biotransformation

Prostaglandin E₁ is very rapidly metabolised. The primary organs for metabolism and inactivation of prostaglandin E₁ are probably the lung, liver and kidney which remove and metabolise 40-95% of the prostaglandin E₁ in a single pass through the organ. A number of other tissues possess lesser, but significant, capacity to metabolise prostaglandin E₁. The predominant metabolites found in plasma, 15-oxo-prostaglandin E1 and 13, 14-dihydro-15 oxo-prostaglandin E₁ are extensively metabolised by β- and ω-oxidation prior to excretion, primarily by the kidney. Few urinary metabolites of prostaglandin E₁ have been characterised, but are widely believed to be analogous to those reported in detail for prostaglandin E₂ and prostaglandin F₂.

Elimination

Excretion is essentially complete within 24 hours after dosing, with no intact prostaglandin E₁ being found in urine and no evidence of tissue retention of prostaglandin E₁ or metabolites. In three species (rat, rabbit and lamb), the prostaglandin metabolising activity of lung from near-term foetal animals has been shown to be at least as effective as that of adults.

In rats, high doses of prostaglandin E₁ increased foetal resorption, presumably due to maternal stress. High concentrations of alprostadil (400 microgram/ml) had no effect on human sperm motility or viability in vitro. In rabbits, there was no foetal damage or effect on reproductive function at the maximum tested intravaginal dose of 4mg.

In the majority of in vitro and in vivo genotoxicity test systems in which alprostadil has been evaluated it produced negative results. These tests include the bacterial reversion test using Salmonella typhimurium, unscheduled DNA synthesis in rat primary hepatocytes, forward mutation assay at the hprt locus in cultured ovary cells from Chinese hamsters, alkaline elution test, sister chromatid exchange assay (all in vitro tests) and the micronucleus test in both mice and rats (in vivo tests). In two other in vitro tests, the mouse lymphoma forward mutation assay and the Chinese hamster ovary chromosomal aberration assay, alprostadil produced borderline positive and positive evidence, respectively, for chromosomal damage. In view of the number of negative in vitro results and the lack of evidence for genotoxicity in two in vivo tests, it is considered that the positive results obtained in these two in vitro tests are of doubtful biological significance. Overall the presently available evidence cannot fully exclude the risk of genotoxic activity in humans.

Long-term carcinogenicity and fertility studies have not been done. The Ames and Alkaline Elution assays reveal no potential for mutagenesis.