title: Dose-dependent pharmacokinetics of MK-417, a potent carbonic anhydrase inhibitor, in rabbits following single and multiple doses.
abstract: MK-417, a potent carbonic anhydrase inhibitor capable of reducing intraocular pressure after topical application, is currently under investigation for the treatment of glaucoma. The purposes of this study were to characterize dose-dependent pharmacokinetics of MK-417 and to determine the accumulating effect of the drug during chronic topical administration in rabbits. Because the drug resided primarily in the erythrocytes, kinetic analyses were performed on whole blood concentration data. Following i.v. administration, both total blood clearance and apparent volume of distribution for MK-417 increased disproportionately between the low and high dose, while the half-life of the drug appeared to be independent of dose. Total blood clearance and apparent volume of distribution increased from 0.993 +/- 0.224 ml/hr/kg (mean +/- SD) and 88.6 +/- 9.4 ml/kg at a dose of 0.05 mg/kg to 2.73 +/- 0.17 ml/hr/kg and 272 +/- 5.5 ml/kg at a dose of 1 mg/kg. The dose-dependent kinetics of MK-417 are probably due to the saturable binding of carbonic anhydrase. Upon instillation of MK-417 into the eyes, the drug was rapidly and well absorbed. At the low dose of 0.05 mg/kg, the bioavailability varied from 58% to 98.5% with a mean value of 76.5 +/- 20.5%. Prediction of concentrations of MK-417 during chronic topical administration were performed based on the corresponding concentrations after a single topical dose using an overlay technique. Good agreement between the experimental data and the predicted blood concentrations of MK-417 during chronic dosing at 0.05 mg/kg, but not at 1 mg/kg, strongly suggests that linear kinetics apply in the case of the low dose but not in the case of the high dose.
authors.affiliation: Merck Sharp & Dohme Research Laboratories, West Point, PA 19486.
authors.forename: J H
authors.initials: JH
authors.lastname: Lin
authors.forename: I W
authors.initials: IW
authors.lastname: Chen
authors.forename: E H
authors.initials: EH
authors.lastname: Ulm
authors.forename: J R
authors.initials: JR
authors.lastname: Gehret
authors.forename: D E
authors.initials: DE
authors.lastname: Duggan
mesh_terms: D000818:Animals; D001682:Biological Availability; D001798:Blood Proteins / Q000378:metabolism; D002257:Carbonic Anhydrase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid; D004912:Erythrocytes / Q000378:metabolism; D066298:In Vitro Techniques; D007408:Intestinal Absorption; D008297:Male; D011485:Protein Binding; D011817:Rabbits; D013449:Sulfonamides / Q000008:administration & dosage / Q000493:pharmacokinetics*; D013876:Thiophenes / Q000008:administration & dosage / Q000493:pharmacokinetics*
chemical_list: D001798:Blood Proteins; D002257:Carbonic Anhydrase Inhibitors; D013449:Sulfonamides; D013876:Thiophenes; C057921:sezolamide