BLOOD DISPOSITION AND URINARY-EXCRETION KINETICS OF METHAZOLAMIDE FOLLOWING ORAL-ADMINISTRATION TO HUMAN-SUBJECTS

The pharmacokinetic disposition of methazolamide (MTZ) was studied in five healthy volunteers following administration of a single oral dose . Drug concentrations in blood, plasma, and urine were measured by HPL C. Over the range of plasma concentrations observed in vivo, MTZ free fraction (measured by ultrafiltration) was 0.28. Being a carbonic anhy drase inhibitor, MTZ would be expected to distribute into, and be sequ estered by, red blood cells. For this reason, MTZ disposition was char acterized utilizing blood concentrations as the reference. Using a two -compartment model, a series of differential equations were simultaneo usly fitted to blood concentrations and urinary excretion data generat ing estimates for k(10) (0.035 +/- 0.019 h(-1)), k(12) (0.200 +/- 0.03 6 h(-1)), k(21) (0.077 +/- 0.046 h(-1)), k(a) (0.304 +/- 0.064 h(-1)), V-c (1.1 +/- 0.18 L) and f(r) (fraction excreted renally, 0.61 +/- 0. 14). Total blood clearance was 0.037 +/- 0.020 L h(-1). The model esti mate of elimination half-life (126 +/- 61 h) was consistent with drug binding to a high affinity carbonic anhydrase isozyme in the erythocyt e. Estimates of MTZ renal clearance and renal excretion ratio were 0.0 21 +/- 0.010 L h(-1) and 0.16 +/- 0.06, respectively. Overall, the pro longed elimination of MTZ from the blood is the result of extensive er ythrocyte distribution and tubular reabsorption by the kidney. (C) 199 8 John Wiley & Sons, Ltd.