12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Alprostadil induces erection by relaxation of trabecular smooth muscle and by dilation of cavernosal arteries. This leads to expansion of lacunar spaces and entrapment of blood by compressing the venules against the tunica albuginea, a process referred to as the corporal veno-occlusive mechanism.
Absorption: For the treatment of erectile dysfunction, alprostadil is administered by injection into the corpora cavernosa. The absolute bioavailability of alprostadil has not been determined.
Distribution: Following intracavernosal injection of 20 mcg alprostadil, mean peripheral plasma concentrations of alprostadil at 30 and 60 minutes after injection (89 and 102 picograms/mL, respectively) were not significantly greater than baseline levels of endogenous alprostadil (96 picograms/mL). Plasma levels of alprostadil were measured using a radioimmunoassay method. Alprostadil is bound in plasma primarily to albumin (81% bound) and to a lesser extent α-globulin IV-4 fraction (55% bound). No significant binding to erythrocytes or white blood cells was observed.
Metabolism: Alprostadil is converted to compounds, which are further metabolized prior to excretion. Following intravenous administration, approximately 80% of circulating alprostadil is metabolized in one pass through the lungs, primarily by beta- and omega-oxidation. Following intracavernosal injection of 20 mcg alprostadil, peripheral levels of the major circulating metabolite, 13, 14-dihydro-15-oxo-PGE1, increased to reach a peak 30 minutes after injection and returned to pre-dose levels by 60 minutes after injection.
Excretion: The metabolites of alprostadil are excreted primarily by the kidney, with almost 90% of an administered intravenous dose excreted in urine within 24 hours post-dose. The remainder of the dose is excreted in the feces. There is no evidence of tissue retention of alprostadil or its metabolites following intravenous administration.
Pharmacokinetics in Specific Populations
Geriatric: The potential effect of age on the pharmacokinetics of alprostadil has not been formally evaluated.
Race: The potential effect of race on the pharmacokinetics of alprostadil has not been formally evaluated.