Dr. Taft et al., BLOOD DISPOSITION AND URINARY-EXCRETION KINETICS OF METHAZOLAMIDE FOLLOWING ORAL-ADMINISTRATION TO HUMAN-SUBJECTS, Biopharmaceutics & drug disposition, 19(6), 1998, pp. 373-380
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.