A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Trental Pharmacology, Pharmacokinetics, Studies, Metabolism - Pentoxifylline
Trental Pharmacology, Pharmacokinetics, Studies, Metabolism - Pentoxifylline
CLINICAL PHARMACOLOGY
Mode of Action
Pentoxifylline and its metabolites improve the flow
properties of blood by decreasing its viscosity. In
patients with chronic
peripheral arterial
disease, this increases blood
flow to the affected microcirculation
and enhances tissue oxygenation.
The precise mode of action
of pentoxifylline and the sequence
of events leading to clinical
improvement are still to be defined. Pentoxifylline administration
has been shown to produce dose-related hemorrheologic effects, lowering
blood viscosity, and improving
erythrocyte flexibility. Leukocyte properties of hemorrheologic
importance have been modified in animal
and in vitro human
studies. Pentoxifylline has been shown to increase leukocyte
deformability
and to inhibit neutrophil adhesion and activation. Tissue oxygen
levels have been shown to be significantly increased by therapeutic
doses of pentoxifylline
in patients with peripheral arterial disease.
Pharmacokinetics and Metabolism
After oral administration
in aqueous solution
pentoxifylline
is almost completely absorbed. It undergoes a first-pass effect
and the various metabolites appear in plasma
very soon after dosing. Peak plasma
levels of the parent compound and its metabolites are reached within
1 hour. The major metabolites are Metabolite l (1-[5-hydroxyhexyl]-3,7-dimethylxanthine)
and Metabolite V (1-[3-carboxypropyl]-3,7-dimethylxanthine), and
plasma levels of these
metabolites are 5 and 8 times greater, respectively, than pentoxifylline.
Following oral administration
of aqueous solutions
containing 100 to 400 mg of pentoxifylline, the pharmacokinetics
of the parent compound
and Metabolite l are dose-related and not proportional (non-linear),
with half-life and
area under the blood-level time
curve (AUC) increasing
with dose. The elimination kinetics of Metabolite V are not dose-dependent.
The apparent plasma
half-life of pentoxifylline
varies from 0.4 to 0.8 hours and the apparent
plasma half-lives of its metabolites vary from 1 to 1.6 hours. There
is no evidence of accumulation
or enzyme induction
(Cytochrome P450) following multiple oral doses.
Excretion is almost totally urinary; the main
biotransformation
product is Metabolite V. Essentially no
parent drug
is found in the urine. Despite large variations in plasma
levels of parent compound
and its metabolites, the urinary
recovery of Metabolite
V is consistent and shows dose
proportionality. Less than 4% of the administered dose
is recovered in feces. Food intake shortly before dosing delays
absorption of an
immediate-release dosage form but does not affect
total absorption. The pharmacokinetics
and metabolism of TRENTAL have not been studied in patients with
renal and/or hepatic dysfunction,
but AUC was increased and
elimination rate
decreased in an older population
(60-68 years) compared to younger individuals (22-30 years).
After administration
of the 400 mg controlled-release
TRENTAL tablet, plasma
levels of the parent
compound and its metabolites
reach their maximum
within 2 to 4 hours and remain constant
over an extended period
of time. Coadministration of TRENTAL tablets with meals resulted
in an increase in mean
Cmax and AUC
by about 28% and 13% for pentoxifylline, respectively. Cmax
for metabolite 1
also increased by about 20%. The controlled release
of pentoxifylline from the tablet
eliminates peaks and troughs in plasma
levels for improved gastrointestinal
tolerance.
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