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Blood disposition and urinary excretion kinetics of methazolamide following oral administration to human subjects
Author(s) -
Taft David R.,
Nordt Sean,
Iyer Ganesh R.,
Schwenk Michael H.
Publication year - 1998
Publication title -
biopharmaceutics and drug disposition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.419
H-Index - 58
eISSN - 1099-081X
pISSN - 0142-2782
DOI - 10.1002/(sici)1099-081x(199809)19:6<373::aid-bdd113>3.0.co;2-t
Subject(s) - disposition , oral administration , pharmacokinetics , urinary system , pharmacology , kinetics , medicine , excretion , endocrinology , psychology , social psychology , physics , quantum mechanics
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 HPLC. Over the range of plasma concentrations observed in vivo , MTZ free fraction (measured by ultrafiltration) was 0.28. Being a carbonic anhydrase inhibitor, MTZ would be expected to distribute into, and be sequestered by, red blood cells. For this reason, MTZ disposition was characterized utilizing blood concentrations as the reference. Using a two‐compartment model, a series of differential equations were simultaneously fitted to blood concentrations and urinary excretion data generating estimates for k 10 (0.035±0.019 h −1 ), k 12 (0.200±0.036 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 estimate of elimination half‐life (126±61 h) was consistent with drug binding to a high affinity carbonic anhydrase isozyme in the erythocyte. Estimates of MTZ renal clearance and renal excretion ratio were 0.021±0.010 L h −1 and 0.16±0.06, respectively. Overall, the prolonged elimination of MTZ from the blood is the result of extensive erythrocyte distribution and tubular reabsorption by the kidney. © 1998 John Wiley & Sons, Ltd.