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Salicylate clearance, the resultant of protein binding and metabolism
Author(s) -
Furst Daniel E.,
Tozer Thomas N.,
Melmon Kenneth L.
Publication year - 1979
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1002/cpt1979263380
Subject(s) - chemistry , aspirin , metabolism , free fraction , plasma clearance , steady state (chemistry) , coefficient of variation , clearance , plasma protein binding , blood proteins , salicylic acid , clearance rate , pharmacology , pharmacokinetics , chromatography , medicine , biochemistry , urology
Steady‐state plasma salicylate concentrations and protein binding were examined in 9 normal subjects to determine relationships among daily dose, total and unbound salicylate concentrations, and total and unbound clearances. Aspirin doses ranging from 0.66 to 4.0 mglkglhr were given to steady state. Free and total salicylate concentrations were measured with spectrophotometric, fluorimetrie, and equilibrium dialysis techniques. Although unbound clearance decreased over the therapeutic range, total clearance was unchanged. The former is a consequence of saturable metabolism; the latter, of saturable plasma protein binding as well as saturable metabolism. The fraction unbound increased linearly with unbound concentration. Clearance determined at 1.8 mglkglhr was used to predict levels obtained at higher aspirin doses. Analysis of residuals was used to ascertain the accuracy of the prediction. The coefficient of variation from prediction among subjects was found to be ±14%. It is concluded that, in normal subjects, salicylate clearance changes relatively little over the therapeutic range because the increasing fraction unbound compensates for decreasing clearance of unbound drug.