Alprostadil has a wide variety of pharmacological actions; vasodilation
and inhibition of platelet aggregation are among the most notable of these
effects. In most animal species tested, alprostadil relaxed retractor penis
and corpus cavernosum urethrae in vitro. Alprostadil also relaxed
isolated preparations of human corpus cavernosum and spongiosum, as well
as cavernous arterial segments contracted by either noradrenaline or PGF2ain
vitro. In pigtail monkeys (Macaca nemestrina), alprostadil increased
cavernous arterial blood flow in vivo. The degree and duration of
cavernous smooth muscle relaxation in this animal model was dose-dependent.
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.
Pharmacokinetics
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 I-globulin IV-4 fraction (55% bound). No significant binding
to erythrocytes or white blood cells was observed.
Metabolism: Alprostadil is rapidly 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. Hence, any alprostadil
entering the systemic circulation following intracavernosal injection is
very rapidly metabolized. 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 Special Populations
Geriatric: The potential effect of age on the pharmacokinetics
of alprostadil has not been formally evaluated. In patients with acute respiratory
distress syndrome (ARDS), the mean (± SD) pulmonary extraction of alprostadil
was 72% ± 15% in 11 elderly patients aged 65 years or older (mean, 71 ±
6 years) and 65% ± 20% in 6 young patients aged 35 years or younger (mean,
28 ± 5 years).
Pediatric: Alprostadil plasma concentrations were measured in
10 neonates (gestational age of 34 weeks in 2 infants and 38 to 40 weeks
in 8 infants) receiving steady-state intravenous infusions of alprostadil
to treat underlying cardiac malformations. Infusion rates of alprostadil
ranged from 5 to 50 (median, 45) nanograms/kilogram/minute, resulting in
alprostadil plasma concentrations ranging between 22 and 530 (median, 56)
picograms/mL. The wide range of alprostadil plasma concentrations in neonates
reflects high variability in individual clearances of alprostadil in this
patient population.
Gender: The potential influence of gender on the pharmacokinetics
of alprostadil has not been formally studied in healthy subjects. Two studies
determined the pulmonary extraction of alprostadil following intravascular
administration in 23 patients with ARDS. The mean (± SD) pulmonary extraction
was 66% ± 20% in 17 male patients and 69% ± 18% in 6 female patients, suggesting
that the pharmacokinetics of alprostadil are not influenced by gender.
Race: The potential influence of race in the pharmacokinetics
of alprostadil has not been formally evaluated.
Renal and Hepatic Insufficiency: The pharmacokinetics of alprostadil
have not been formally studied in patients with renal or hepatic insufficiency.
Pulmonary Disease: The pulmonary extraction of alprostadil following
intravascular administration was reduced by 15% (66 ± 3.2% vs. 78 ± 2.4%)
in patients with ARDS compared with a control group of patients with normal
respiratory function who were undergoing cardiopulmonary bypass surgery.
Pulmonary clearance was found to vary as a function of cardiac output and
pulmonary intrinsic clearance in a group of 14 patients with ARDS or at
risk of developing ARDS following trauma or sepsis. In this study, the extraction
efficiency of alprostadil ranged from subnormal (11%) to normal (90%), with
an overall mean of 67%.
Drug-Drug Interactions: The potential for pharmacokinetic drug-drug
interactions between alprostadil and other agents has not been formally
studied.