CLINICAL PHARMACOLOGY
Pharmacokinetics
Misoprostol is extensively absorbed, and undergoes rapid
de-esterification to its free acid, which is responsible for its clinical
activity and, unlike the parent compound, is detectable in plasma. The alpha
side chain undergoes beta oxidation and the beta side chain undergoes omega
oxidation followed by reduction of the ketone to give prostaglandin F
analogs.
In normal volunteers, misoprostol is rapidly absorbed after oral
administration with a Tmax of misoprostol acid of 12 ± 3
minutes and a terminal half-life of 20—40 minutes.
There is high variability of plasma levels of misoprostol acid between and
within studies but mean values after single doses show a linear relationship
with dose over the range of 200-400 mcg. No accumulation of misoprostol acid was
noted in multiple dose studies; plasma steady state was achieved within two
days.
Maximum plasma concentrations of misoprostol acid are diminished when the
dose is taken with food and total availability of misoprostol acid is reduced by
use of concomitant antacid. Clinical trials were conducted with concomitant
antacid, however, so this effect does not appear to be clinically important.
After oral administration of radiolabeled misoprostol, about 80% of detected
radioactivity appears in urine. Pharmacokinetic studies in patients with varying
degrees of renal impairment showed an approximate doubling of T1/2, Cmax, and AUC compared to normals,
but no clear correlation between the degree of impairment and AUC. In subjects
over 64 years of age, the AUC for misoprostol acid is increased. No routine
dosage adjustment is recommended in older patients or patients with renal
impairment, but dosage may need to be reduced if the usual dose is not
tolerated.
Misoprostol does not affect the hepatic mixed function oxidase (cytochrome
P-450) enzyme systems in animals.
Drug interaction studies between misoprostol and several nonsteroidal
anti-inflammatory drugs showed no effect on the kinetics of ibuprofen or
diclofenac, and a 20% decrease in aspirin AUC, not thought to be clinically
significant.
Pharmacokinetic studies also showed a lack of drug interaction with
antipyrine and propranolol when these drugs were given with misoprostol.
Misoprostol given for 1 week had no effect on the steady state pharmacokinetics
of diazepam when the two drugs were administered 2 hours apart.
The serum protein binding of misoprostol acid is less than 90% and is
concentration-independent in the therapeutic range.
Pharmacodynamics
Misoprostol has both antisecretory (inhibiting gastric acid
secretion) and (in animals) mucosal protective properties. NSAIDs inhibit
prostaglandin synthesis, and a deficiency of prostaglandins within the gastric
mucosa may lead to diminishing bicarbonate and mucus secretion and may
contribute to the mucosal damage caused by these agents. Misoprostol can
increase bicarbonate and mucus production, but in man this has been shown at
doses 200 mcg and above that are also antisecretory. It is therefore not
possible to tell whether the ability of misoprostol to reduce the risk of
gastric ulcer is the result of its antisecretory effect, its mucosal protective
effect, or both.
In vitro studies on canine parietal cells using
tritiated misoprostol acid as the ligand have led to the identification and
characterization of specific prostaglandin receptors. Receptor binding is
saturable, reversible, and stereospecific. The sites have a high affinity for
misoprostol, for its acid metabolite, and for other E type prostaglandins, but
not for F or I prostaglandins and other unrelated compounds, such as histamine
or cimetidine. Receptor-site affinity for misoprostol correlates well with an
indirect index of antisecretory activity. It is likely that these specific
receptors allow misoprostol taken with food to be effective topically, despite
the lower serum concentrations attained.
Misoprostol produces a moderate decrease in pepsin concentration during basal
conditions, but not during histamine stimulation. It has no significant effect
on fasting or postprandial gastrin nor on intrinsic factor output
Effects on gastric acid secretion
Misoprostol, over the range of 50—200 mcg, inhibits basal and nocturnal gastric
acid secretion, and acid secretion in response to a variety of stimuli,
including meals, histamine, pentagastrin, and coffee. Activity is apparent 30
minutes after oral administration and persists for at least 3 hours. In general,
the effects of 50 mcg were modest and shorter lived, and only the 200-mcg dose
had substantial effects on nocturnal secretion or on histamine and
meal-stimulated secretion
Uterine effects
Misoprostol has been shown to produce uterine contractions that may endanger
pregnancy. (See boxed WARNINGS.)
Other pharmacologic effects
Misoprostol does not produce clinically significant effects on serum levels of
prolactin, gonadotropins, thyroid-stimulating hormone, growth hormone,
thyroxine, cortisol, gastrointestinal hormones (somatostatin, gastrin,
vasoactive intestinal polypeptide, and motilin), creatinine, or uric acid.
Gastric emptying, immunologic competence, platelet aggregation, pulmonary
function, or the cardiovascular system are not modified by recommended doses of
misoprostol.
Clinical Studies
In a series of small short-term (about 1 week) placebo-controlled studies in
healthy human volunteers, doses of misoprostol were evaluated for their ability
to reduce the risk of NSAID-induced mucosal injury. Studies of 200 mcg q.i.d. of
misoprostol with tolmetin and naproxen, and of 100 and 200 mcg q.i.d. with
ibuprofen, all showed reduction of the rate of significant endoscopic injury
from about 70—75% on placebo to 10—30% on misoprostol. Doses of 25—200 mcg
q.i.d. reduced aspirin-induced mucosal injury and bleeding.
Reducing the Risk of Gastric Ulcers Caused by Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)
Two 12-week, randomized, double-blind trials in osteoarthritic patients who had
gastrointestinal symptoms but no ulcer on endoscopy while taking an NSAID
compared the ability of 200 mcg of misoprostol, 100 mcg of misoprostol, and
placebo to reduce the risk of gastric ulcer (GU) formation. Patients were
approximately equally divided between ibuprofen, piroxicam, and naproxen, and
continued this treatment throughout the 12 weeks. The 200-mcg dose caused a
marked, statistically significant reduction in gastric ulcers in both studies.
The lower dose was somewhat less effective, with a significant result in only
one of the studies.
In these trials there were no significant differences between misoprostol and
placebo in relief of day or night abdominal pain. No effect of misoprostol in
reducing the risk of duodenal ulcers was demonstrated, but relatively few
duodenal lesions were seen.
In another clinical trial, 239 patients receiving aspirin 650—1300 mg q.i.d.
for rheumatoid arthritis who had endoscopic evidence of duodenal and/or gastric
inflammation were randomized to misoprostol 200 mcg q.i.d. or placebo for 8
weeks while continuing to receive aspirin. The study evaluated the possible
interference of misoprostol on the efficacy of aspirin in these patients with
rheumatoid arthritis by analyzing joint tenderness, joint swelling, physician's
clinical assessment, patient's assessment, change in ARA classification, change
in handgrip strength, change in duration of morning stiffness, patient's
assessment of pain at rest, movement, interference with daily activity, and ESR.
Misoprostol did not interfere with the efficacy of aspirin in these patients
with rheumatoid arthritis.
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