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D,
E,
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Glucotrol Pharmacology, Pharmacokinetics, Studies, Metabolism - Glipizide
Glucotrol Pharmacology, Pharmacokinetics, Studies, Metabolism - Glipizide
CLINICAL PHARMACOLOGY
Immediate Release Tablets
Mechanism of Action
The primary mode of action
of glipizide in experimental
animals appears to be the stimulation
of insulin secretion
from the beta cells of
pancreatic islet tissue
and is thus dependent on functioning beta
cells in the pancreatic islets. In
humans glipizide appears
to lower the blood glucose
acutely by stimulating the release
of insulin from the
pancreas, an effect dependent
upon functioning beta cells
in the pancreatic
islets. The mechanism
by which glipizide
lowers blood glucose
during long-term administration
has not been clearly established. In
man, stimulation
of insulin secretion
by glipizide in response
to a meal is undoubtedly
of major importance. Fasting insulin
levels are not elevated even on long-term glipizide
administration, but the postprandial
insulin response
continues to be enhanced after at least 6 months of treatment. The
insulinotropic response
to a meal occurs within
30 minutes after an oral
dose of glipizide
in diabetic patients,
but elevated insulin
levels do not persist beyond the time
of the meal challenge. Extrapancreatic effects may play a party
in the mechanism of
action of oral sulfonylurea
hypoglycemic drugs.
Blood sugar control
persists in some patients for up to 24 hours after a single dose
of glipizide, even though plasma
levels have declined to a small fraction
of peak levels by that time
(see Pharmacokinetics).
Some patients fail to respond initially, or gradually lose their
responsiveness to sulfonylurea
drugs, including glipizide. Alternatively, glipizide
may be effective in some patients who have not responded or have
ceased to respond to other sulfonylureas.
Pharmacokinetics
Gastrointestinal absorption
of glipizide in man
is uniform, rapid, and essentially complete. Peak plasma
concentrations occur 1-3 hours after a single oral
dose. The half-life
of elimination ranges
from 2-4 hours in normal
subjects, whether given intravenously or orally. The metabolic and
excretory patterns are similar with the two routes of administration,
indicating that first-pass metabolism
is not significant. Glipizide does not accumulate in plasma
on repeated oral administration.
It has been reported that total absorption
and disposition
of an oral dose
was unaffected by food in normal
volunteers, but absorption
was delayed by about 40 minutes. Thus glipizide
was more effective when administered about 30 minutes before, rather
than with, a test meal
in diabetic patients.
Protein binding was studied in serum
from volunteers who received either oral
or intravenous glipizide and found to be 98-99% one hour after either
route of administration. The apparent
volume of distribution
of glipizide after
intravenous administration
was 11 liters, indicative of localization
within the extracellular
fluid compartment. In mice
no glipizide or metabolites
were detectable autoradiographically in the brain
or spinal cord
of males or females, nor in the fetuses of pregnant females. In
another study, however, very small amounts of radioactivity were
detected in the fetuses of rats given labelled drug.
The metabolism of
glipizide is extensive
and occurs mainly in the liver. The primary metabolites are inactive
hydroxylation products and polar
conjugates and are excreted mainly in the urine. Less than 10% unchanged
glipizide is found in the urine.
Extended Release Tablets
Mechanism of Action
Glipizide appears to lower blood
glucose acutely by stimulating
the release of insulin
from the pancreas, an effect
dependent upon functioning beta cells in the pancreatic
islets. Extrapancreatic effects also may play a party
in the mechanism of
action of oral
sulfonylurea hypoglycemic
drugs. Two extrapancreatic effects shown to be important in the
action of glipizide are
an increase in insulin
sensitivity and a decrease in hepatic
glucose production. However, the mechanism
by which glipizide
lowers blood glucose during
long-term administration
has not been clearly established. Stimulation of insulin
secretion by glipizide
in response to a meal
is of major importance. The insulinotropic response
to a meal is enhanced with
glipizide extended-release
administration in diabetic
patients. The postprandial
insulin and C-peptide
responses continue to be enhanced after at least 6 months of treatment.
In 2 randomized, double
blind, dose-response studies comprising a total of 347 patients,
there was no significant
increase in fasting
insulin in all glipizide
extended-release-treated patients combined compared to placebo,
although minor elevations
were observed at some doses. There was no increase in fasting
insulin over the long-term.
Some patients fail to respond initially, or gradually lose their
responsiveness to sulfonylurea
drugs, including glipizide. Alternatively, glipizide
may be effective in some patients who have not responded or have
ceased to respond to other sulfonylurea.
Effects on Blood Glucose
The effectiveness
of glipizide extended-release
tablets in NIDDM at doses
from 5-60 mg once daily has
been evaluated in 4 therapeutic
clinical trials each with long-term open
extensions involving a total 598 patients. Once daily administration
of 5, 10, and 20 mg produced
statistically significant reductions from placebo
in hemoglobin A1C,
fasting plasma
glucose and postprandial
glucose in mild to severe
NIDDM patients. In
a pooled analysis of the patients treated with 5 mg
and 20 mg, the relationship between dose
and glipizide extended-release's
effect of reducing hemoglobin
A1C was not established. However, in the case
of fasting plasma glucose
patients treated with 20 mg
had a statistically significant
reduction of fasting
plasma glucose
compared to the 5 mg-treated group.
The reductions in hemoglobin
A1C and fasting
plasma glucose were similar
in younger and older patients. Efficacy of glipizide
extended-release was not affected by gender, race, or weight
(as assessed by body mass
index). In long term extension
trials, efficacy of glipizide
extended-release was maintained in 81% of patients for up to 12
months.
In an open, two-way crossover
study 132 patients were randomly assigned to either glipizide
extended-release or glipizide
for 8 weeks and then crossed over to the other drug
for an additional 8 weeks. Glipizide extended-release administration
resulted in significantly lower fasting
plasma glucose
levels and equivalent
hemoglobin A1C
levels, as compared to glipizide.
Pharmacokinetics and Metabolism
Glipizide is rapidly and completely absorbed following oral
administration in an immediate
release dosage
form. The absolute
bioavailability of glipizide was 100% after single doses in patients
with NIDDM. Beginning 2 to 3 hours after administration
of glipizide extended-release
tablets, plasma drug
concentrations gradually rise reaching maximum
concentrations within 6 to 12 hours after dosing. With subsequent
once daily dosing of glipizide extended-release tablets, effective
plasma glipizide
concentrations are maintained throughout the 24 hour dosing interval
with less peak to through fluctuation than that observed with twice
daily dosing of immediate
release glipizide. The mean
relative bioavailability of glipizide
in 21 males with NIDDM after administration
of 20 mg glipizide
extended-release tablets, compared to immediate
release glipizide
(10 mg given twice daily),
was 90% at steady state. Steady state
plasma concentrations
were achieved by at least the fifth day of dosing with glipizide
extended-release tablets in 21 male
with NIDDM and patients
younger than 65 years. Approximately 1 to 2 days longer were required
to reach steady state
in 24 elderly (³65 years) males
and females with NIDDM. No accumulation of drug
was observed in patients with NIDDM
during chronic dosing
with glipizide extended-release
tablets. Administration of glipizide
extended-release with food
has no effect on the 2 to 3 hour lag
time in drug
absorption. In a single dose,
food effect study in
21 healthy males subjects, the administration
of glipizide extended-release immediately before a high fat
breakfast resulted in a 40% increase in the glipizide
mean Cmax value,
which was significant, but the effect
on the AUC was not significant.
There was no change in glucose response between the fed and fasting
state. Markedly reduced GI
retention times of the glipizide
extended-release tablets over prolonged periods (e.g., short
bowel syndrome) may influence
the pharmacokinetic profile of the drug
and potentially result in lower plasma
concentrations. In a multiple
dose study in 26 males
with NIDDM, the pharmacokinetics
of glipizide were linear
over the dose range
of 5 to 60 mg of glipizide
extended-release in that the plasma
drug concentrations increased
proportionately with dose. In a single dose
study in 24 healthy subjects, four 5 mg, two 10 mg, and one 20 mg
glipizide extended-release
tablets were bioequivalent.
Glipizide is eliminated primarily by hepatic
biotransformation: less than 10% of a dose
is excreted as unchanged drug
in urine and feces; approximately
90% of a dose is excreted
as biotransformation
products in urine (80%)
and feces (10%). The major
metabolites of glipizide
are products of aromatic hydroxylation and have no hypoglycemic
activity. A minor metabolite
which accounts for less than 2% of a dose, an acetylaminoethyl benzine
derivatives, is reported to have 1/10 to 1/3 as much hypoglycemic
activity as the parent compound. The mean
total body clearance
of glipizide was approximately
3 liters per hour after
single intravenous
doses in patients with NIDDM. The mean
apparent volume
of distribution
was approximately 10 liters. Glipizide is 98-99% bound
to serum proteins, primarily
to albumin. The mean terminal
elimination half-life
of glipizide ranged
from 2 to 5 hours after single or multiple
doses in patients with NIDDM. There were no significant
differences in the pharmacokinetics
of glipizide after
single dose administration
to older diabetic subjects
compared to younger healthy subjects. There is only limited information
regarding the effects of renal
impairment on the
disposition of glipizide
and no information regarding the effects of hepatic disease. However,
since glipizide is
highly protein bound
and hepatic biotransformation
is the predominant route of elimination
the pharmacokinetics
and/or pharmacodynamics of glipizide
may be altered in patients with renal
or hepatic impairment.
In mice no glipizide
or metabolites were detectable autoradiographically in the brain
or spinal cord
of males or females, nor in the fetuses of pregnant females. In
another study, however, very small amounts of radioactivity were
detected in the fetuses of rats given labeled drug.
Immediate and Extended Release Tablets
Other Effects: It has been shown that glipizide
therapy was effective in controlling blood
sugar without deleterious
changes in the plasma
lipoprotein profiles
of patients treated for NIDDM.
In a placebo-controlled, crossover
study in normal volunteers,
glipizide had no anti-diuretic activity, and, in fact, led to a
slight increase in free water
clearance.
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