緑内障治療薬アセタゾラミドの体内動態と薬効の速度論的解析

Abstract

Although acetazolamide, a carbonic anhydrase inhibitor, has an effect of lowering the intraocular pressure, a number of side effects have been reported with its use.We therefore investigated the pharmacokinetics and pharmacodynamics of acetazolamide in patients with an intraocular pressure (IOP) elevation. The plasma acetazolamide concentration and IOP in 17 patients with a transient IOP elevation were simultaneously measured after the last acetazolamide administration, and the findings were analyzed by nonlinear mixed effect modeling using the NONMEM software program. The plasma concentration profile of acetazolamide was characterized by a one-compartment model with first-order absorption.The apparent oral clearance (L/hr) showed a correlation with the creatinine clearance (CCR, mL/min), as estimated by the Cockcroft and Gault equation, as follows : 0.0468·CCR. The estimated apparent oral volume of the distribution, first-order absorption rate constant, and absorption lag time were 0.231 L/kg, 0.821 hr-1, and 0.497 hr, respectively. The intraocular pressure after oral acetazolamide administration was characterized by an Emax model. The maximal effect in lowering the IOP (Emax) was 7.2 mmHg, and the concentration corresponding to 50% of Emax (EC50) was 1.64 μg/mL. We next investigated the relationship between the acetazolamide concentration and its side effects in 23 glaucomatous patients who received repeated doses of oral acetazolamide for one week or more. The serum concentration of chloride ion was found to be higher than the normal range, and also showed a significant correlation with the acetazolamide concentration in the erythrocytes. The patients with an erythrocyte acetazolamide concentration of more than 20μg/mL had higher incidents of the side effects. Based on these results, the recommended dosage of acetazolamide was calculated so that the minimum plasma concentration at steady-state exceeded 4μg/ mL. The dosage regimen desired in this study is expected to contribute to the safe and effective pharmacotherapeutic use of acetazolamide.