Pharmacodynamics and pharmacokinetics of diclofenac sodium
Diclofenac sodium is a nonsteroidal anti-inflammatory drug (NSAID). In
pharmacologic studies, diclofenac sodium has shown anti-inflammatory, analgesic
and antipyretic properties. The mechanism of action of diclofenac sodium,
like other NSAIDs, is not completely understood but may be related to prostaglandin
synthetase inhibition.
Diclofenac sodium is completely absorbed from the GI tract after fasting,
oral administration. The diclofenac sodium in ARTHROTEC is in a pharmaceutical
formulation that resists dissolution in the low pH of gastric fluid but
allows a rapid release of drug in the higher pH environment of the duodenum.
Only 50% of the absorbed dose is systemically available due to first pass
metabolism. Peak plasma levels are achieved in 2 hours (range 1–4 hours),
and the area under the plasma concentration curve (AUC) is dose proportional
within the range of 25 mg to 150 mg. Peak plasma levels are less than dose-proportional and are approximately 1.5 and 2.0 mcg/mL for 50 mg and 75 mg
doses, respectively.
Plasma concentrations of diclofenac sodium decline from peak levels in
a biexponential fashion, with the terminal phase having a half-life of approximately
2 hours. Clearance and volume of distribution are about 350 mL/min and 550
mL/kg, respectively. More than 99% of diclofenac sodium is reversibly bound
to human plasma albumin.
Diclofenac sodium is eliminated through metabolism and subsequent urinary
and biliary excretion of the glucuronide and the sulfate conjugates of the
metabolites. Approximately 65% of the dose is excreted in the urine and
35% in the bile.
Conjugates of unchanged diclofenac account for 5–10% of the dose excreted
in the urine and for less than 5% excreted in the bile. Little or no unchanged
unconjugated drug is excreted. Conjugates of the principal metabolite account
for 20–30% of the dose excreted in the urine and for 10–20% of the dose
excreted in the bile.
Conjugates of three other metabolites together account for 10–20% of
the dose excreted in the urine and for small amounts excreted in the bile.
The elimination half-life values for these metabolites are shorter than
those for the parent drug. Urinary excretion of an additional metabolite
(half-life = 80 hours) accounts for only 1.4% of the oral dose. The degree
of accumulation of diclofenac metabolites is unknown. Some of the metabolites
may have activity.
Pharmacodynamics and pharmacokinetics of misoprostol
Misoprostol is a synthetic prostaglandin E1
analog with gastric antisecretory and (in animals) mucosal protective properties.
NSAIDs inhibit prostaglandin synthesis. A deficiency of prostaglandins within
the gastric and duodenal mucosa may lead to diminishing bicarbonate and
mucus secretion and may contribute to the mucosal damage caused by NSAIDs.
Misoprostol can increase bicarbonate and mucus production, but in humans
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 and duodenal ulcers 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 stereo-specific. 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 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.
Orally administered misoprostol is rapidly and extensively absorbed,
and it undergoes rapid metabolism to its biologically active metabolite,
misoprostol acid. Misoprostol acid in ARTHROTEC reaches a maximum plasma
concentration in about 20 minutes and is, thereafter, quickly eliminated
with an elimination t1/2 of about 30 minutes.
There is high variability in plasma levels of misoprostol acid between and
within studies, but mean values after single doses show a linear relationship
with dose of misoprostol over the range of 200 to 400 mcg. No accumulation
of misoprostol acid was found in multiple-dose studies, and plasma steady
state was achieved within 2 days. The serum protein binding of misoprostol
acid is less than 90% and is concentration-independent in the therapeutic
range.
After oral administration of radio-labeled misoprostol, about 70% of detected
radioactivity appears in the urine. 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; this effect does not appear to
be clinically important.
Pharmacokinetic studies also showed a lack of drug interaction with antipyrine
or propranolol 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.
Pharmacokinetics of ARTHROTEC
The pharmacokinetics following oral administration of a single dose (see
Table 1) or multiple doses of ARTHROTEC (diclofenac sodium/misoprostol)
to healthy subjects under fasted conditions are similar to the pharmacokinetics
of the two individual components.
Table 1. MISOPROSTOL ACID Mean (SD)
The rate and extent of absorption of both diclofenac sodium and misoprostol
acid from ARTHROTEC 50 and ARTHROTEC 75 are similar to those from diclofenac
sodium and misoprostol formulations each administered alone.
Neither diclofenac sodium nor misoprostol acid accumulated in plasma
following repeated doses of ARTHROTEC given every 12 hours under fasted
conditions. Food decreases the multiple-dose bioavailability profile of
ARTHROTEC 50 and ARTHROTEC 75.
Special populations
A 4-week study, comparing plasma level profiles of diclofenac (50 mg bid)
in younger (26–46 years) versus older (66–81 years) adults, did not show
differences between age groups (10 patients per age group). In a multiple-dose
(bid) crossover study of 24 people aged 65 years or older, the misoprostol
contained in ARTHROTEC did not affect the pharmacokinetics of diclofenac
sodium.
Differences in the pharmacokinetics of diclofenac have not been detected
in studies of patients with renal (50 mg intravenously) or hepatic impairment
(100 mg oral solution). In patients with renal impairment (N=5, creatinine
clearance 3 to 42 mL/min), AUC values and elimination rates were comparable
to those in healthy people. In patients with biopsy-confirmed cirrhosis
or chronic active hepatitis (variably elevated transaminases and mildly
elevated bilirubins, N=10), diclofenac concentrations and urinary elimination
values were comparable to those in healthy people.
Pharmacokinetic studies with misoprostol in patients with varying degrees
of renal impairment showed an approximate doubling of t1/2,
Cmax and AUC compared to healthy people. In people
over 64 years of age, the AUC for misoprostol acid is increased.
In a study of people with mild to moderate hepatic impairment, mean misoprostol
acid AUC and Cmax showed approximately double the mean
values obtained in healthy people. Three people who had the lowest antipyrine and
lowest indocyanine green clearance values had the highest misoprostol acid AUC
and Cmax values.
After a single oral dose of misoprostol to nursing mothers, misoprostol acid
was excreted in breast milk. The maximum concentration of misoprostol acid in
expressed breast milk was achieved within 1 hour after dosing and was 7.6 pg/mL
(CV 37%) and 20.9 pg/mL (CV 77%) after single 200 µg and 600 µg misoprostol
administration, respectively. The misoprostol acid concentrations in breast
milk declined to < 1 pg/mL at 5 hours post-dose.