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
Xalatan Pharmacology, Pharmacokinetics, Studies, Metabolism - Latanoprost
Xalatan Pharmacology, Pharmacokinetics, Studies, Metabolism - Latanoprost
CLINICAL PHARMACOLOGY
Mechanism of Action
Latanoprost is a prostanoid selective FP receptor
agonist which is believed
to reduce the intraocular
pressure by increasing
the outflow of aqueous
humor. Studies in animals and humans suggest that the main
mechanism of action
is increased uveoscleral outflow.
Pharmacokinetics and Pharmacodynamics
Absorption: Latanoprost is absorbed through the cornea
where the isopropyl ester
prodrug is hydrolyzed
to the acid form
to become biologically active. Studies in humans indicate that the
peak concentration in the aqueous
humor is reached about
2 hours after topical
administration.
Distribution: The distribution
volume in humans is 0.16
± 0.02 L/kg. The acid
of latanoprost could be measured in aqueous
humor during the first
4 hours, and in plasma only during the first hour after local
administration.
Metabolism: Latanoprost, an isopropyl ester
prodrug, is hydrolyzed by esterases in the cornea
to the biologically active acid. The active acid
of latanoprost reaching the systemic
circulation is primarily
metabolized by the liver
to the 1,2-dinor and 1,2,3,4-tetranor metabolites via fatty acid
b-oxidation.
Elimination: The elimination
of the acid of latanoprost
from human plasma
was rapid (t½ = 17 min) after both intravenous
and topical administration.
Systemic clearance
is approximately 7 ml/min/kg. Following hepatic
b-oxidation, the metabolites are mainly
eliminated via the kidneys.
Approximately 88% and 98% of the administered dose
is recovered in the urine
after topical and intravenous
dosing, respectively.
CLINICAL STUDIES
Patients with mean baseline
intraocular pressure
of 24-25 mmHg who were treated for 6 months in multicenter, randomized,
controlled trials demonstrated 6-8 mmHg reductions in intraocular
pressure. This IOP reduction
with latanoprost 0.005% dosed once daily was equivalent
to the effect of timolol
0.5% dosed twice daily.
ANIMAL PHARMACOLOGY
In monkeys, latanoprost has been shown to induce increased pigmentation
of the iris. The results from the preclinical
program demonstrated
that the increased pigmentation
is unlikely to be associated with proliferation of melanocytes.
It appears that the mechanism
of increased pigmentation is stimulation
of melanin production
in melanocytes of the iris
stroma.
In ocular toxicity studies,
administration
of latanoprost at a dose of 6 mcg/eye/day
(4 times the daily human
dose) to cynomolgus monkeys has also been shown to induce increased
palpebral fissure. This effect
has been reversible
and occurred at doses above the standard clinical
dose level.
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