DOSE-DEPENDENT BIOAVAILABILITY AND METABOLISM OF SALICYLAMIDE IN DOGS

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Abstract
The dose-dependent first-pass metabolism and pharmacokinetics of salicylamide (SAM) were studied at 4 dose levels in 6 dogs. Four min after each oral dose, a tracer dose of [14C]SAM was given i.v. to determine clearance and bioavailability. Over the dosage range studied, 5-40 mg/kg, bioavailability increased from 0.24 .+-. 0.14 (mean .+-. SD) to 0.76 .+-. 0.20 (P < 0.05). Clearance decreased from 3.4 .+-. 1.0 to 0.60 .+-. 0.11 l/min (P < 0.01) and half-life increased from 5.0 .+-. 1.2 to 23.5 .+-. 6.1 min (P < 0.01). Measurement of SAM clearance to individual metabolites indicated that the sulfoconjugation and not the glucuronidation pathway was responsible for the dose-dependent effects observed. These effects occurred even at doses not expected to have caused significant depletion of body stores of inorganic sulfate; the plasma concentration of inorganic sulfate decreased by only a maximum of 13 and 26% after the 5- and 10-mg/kg SAM doses, respectively. When [14C]SAM was given alone in tracer amounts, clearance values greatly exceeded cardiac output. SAM apparently undergoes sulfation in organs other than the liver and intestinal wall.