Pharmacology: Pharmacodynamics: Latanoprost is a prostanoid selective FP receptor agonist that is believed to reduce the intraocular pressure (IOP) by increasing the outflow of aqueous humor. Studies in animals and man suggest that the main mechanism of action is increased uveoscleral outflow. Elevated IOP represents a major risk factor for glaucomatous field loss. The higher the level of IOP, the greater the likelihood of optic nerve damage and visual field loss.
Pharmacokinetics: Absorption: Latanoprost is absorbed through the cornea where the isopropyl ester prodrug is hydrolyzed to the acid form to become biologically active. Studies in man indicate that the peak concentration in the aqueous humor is reached about two hours after topical administration.
Distribution: The distribution volume in humans is 0.16 ± 0.02 L/kg. The acid of latanoprost can 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 β-oxidation.
Excretion: The elimination of the acid of latanoprost from human plasma is rapid (t½=17 min) after both intravenous and topical administration. Systemic clearance is approximately 7 mL/min/kg. Following hepatic β-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.
Toxicology: Carcinogenesis, Mutagenesis, Impairment of Fertility: Latanoprost was not mutagenic in bacteria, in mouse lymphoma or in mouse micronucleus tests.
Chromosome aberrations were observed in vitro with human lymphocytes.
Latanoprost was not carcinogenic in either mice or rats when administered by oral gavage at doses of up to 170 µg/kg/day (approximately 2,800 times the recommended maximum human dose) for up to 20 and 24 months, respectively.
Additional in vitro and in vivo studies on unscheduled DNA synthesis in rats were negative.
Latanoprost has not been found to have any effect on male or female fertility in animal studies.