Detection of the free acid of bimatoprost in aqueous humor samples from human eyes treated with bimatoprost before cataract surgery.

PURPOSE: To determine whether bimatoprost is hydrolyzed to its free acid after topical application in humans in vivo. DESIGN: Prospective, masked, and vehicle controlled. PARTICIPANTS: Thirty-one eyes of 31 patients with cataracts. METHODS: Beginning 7 days before scheduled cataract surgery, one eye of each patient was treated with bimatoprost 0.03% or vehicle once daily, with the last drop administered 2 to 12 hours before anterior chamber paracentesis before cataract surgery. In a masked fashion, aqueous humor specimens were assayed for bimatoprost and its free acid by high-pressure liquid chromatography and mass spectrometry. MAIN OUTCOME MEASURE: Detection of the free acid of bimatoprost in aqueous humor. RESULTS: Aqueous humor concentrations of the free acid of bimatoprost were 22.0+/-7.0 nmol/l (mean +/- standard error of the mean, n = 12) and 7.0+/-4.6 nmol/l (n = 8) at 2 and 12 hours, respectively, and below the limit of detection after vehicle (n = 10). Concentrations of bimatoprost (amide) were 5.7+/-1.4 and 1.1+/-0.4 nmol/l at 2 and 12 hours, respectively, and undetectable after vehicle. CONCLUSION: After topical application of bimatoprost in humans, a sufficient concentration of its free acid, a potent FPprostanoid receptor agonist, is found in the aqueous humor to account for its ability to reduce intraocular pressure.

Ocular and systemic pharmacokinetics of latanoprost in humans.

The ocular pharmacokinetics of latanoprost (13,14-dihydro-17-phenyl-18, 19,20-trinor-PGF(2alpha)-isopropyl ester; Xalatan [Pharmacia-Upjohn, Peapack, NJ]) was studied in patients undergoing cataract surgery using radio-immunoassay, and the systemic pharmacokinetics of latanoprost was studied in healthy human volunteers with 3H-latanoprost as well as radioimmunoassay. After topical application, latanoprost was rapidly hydrolysed in the cornea and blood. The maximum concentration of the active drug, latanoprost acid, was detected in the aqueous humor 1-2 hours after topical administration of the clinical dose and amounted to 15-30 ng/ml. The half-life of latanoprost acid in the aqueous humor was 2-3 hours. In the systemic circulation the peak concentration of latanoprost acid appeared 5 minutes after topical application and reached a level of 53 pg/ml with an elimination half-life of 17 minutes. In patients that had been on the drug continuously for more than 1 year, 5 out of 10 had plasma levels of latanoprost acid below the limit of detection (<30 pg/ml). The mean plasma clearance was 0.40 +/- 0.04 l/h. kg, and the volume of distribution was 0.16 +/- 0.02 l/kg after intravenous administration. The corresponding figures after ocular administration were 0.88 l/h. kg, and 0.36 l/kg. The majority of the radioactivity was recovered in urine (88%) and the rest was found in feces. In the eye the main metabolism of latanoprost was the ester hydrolysis. The only prominent chromatographic peak in plasma corresponded to latanoprost acid. In urine no latanoprost or latanoprost acid was detected. Before excretion latanoprost acid was beta oxidized to 1,2-dinor and 1,2,3,4-tetranor latanoprost acid. These metabolites accounted for approximately 66% of the radioactivity in urine. In conclusion, latanoprost is rapidly hydrolyzed in the eye and blood to latanoprost acid. Minimal further metabolism occurs in the eye, but latanoprost acid undergoes beta oxidation and other metabolism outside the eye. After topical application the peak concentration in aqueous humor was approximately 10(-7) M, whereas that in plasma was about 10(-10) M or less.

Bioavailability in the human eye of a fixed combination of latanoprost and timolol compared to monotherapy.

The ocular pharmacokinetics of a single topical administration of a fixed combination (FC) of latanoprost 0.005% and timolol 0.5% was compared to the monotherapies of latanoprost and timolol in cataract surgery patients. The absorption rate of latanoprost and timolol into the aqueous humor was similar after administration of the FC compared to the two drugs given separately. The aqueous humor concentration of the acid of latanoprost tended to be higher 1-4 hours after administration of FC compared to latanoprost monotherapy. This resulted in an increased AUC. The Tmax and elimination half-life of both latanoprost and timolol were similar after administration of either FC or the two drugs given as monotherapy. Latanoprost did not have any influence on the ocular pharmacokinetics of timolol. The bioavailability of latanoprost and timolol into human aqueous humor, after FC, was at least as good as for the two drugs administered separately.