Nonlinear intestinal first-pass metabolism of salicylamide in dogs after portacaval transposition.

The dose-dependent first-pass metabolism and pharmacokinetics of salicylamide (SAM) were studied at four dose levels in dogs before and after portacaval transposition. Four minutes after each p.o. dose, a tracer dose of [14C]SAM was given i.v. to determine clearance and bioavailability. Over the dosage range studied pretransposition, 5 to 40 mg/kg, bioavailability increased from 0.24 +/- 0.14 (mean +/- S.D.) to 0.76 +/- 0.20 (P less than .05). Clearance decreased from 3.4 +/- 1.0 to 0.6 +/- 0.11 liter/min (P less than .01) and half-life increased from 5.0 +/- 1.2 to 23.5 +/- 6.1 min (P less than .01). Over the dosage range studied post-transposition, 1.5 to 20 mg/kg, bioavailability increased from 0.31 +/- 0.09 to 0.99 +/- 0.08. Clearance and half-life had the same values and showed the same dose-dependence as in the normal dogs. The amount of SAM removed by the intestine during first-pass remained constant at about 1 mg/kg over the dose range given to the post-transposition animals. Therefore, although more easily saturable than the liver, the intestine plays an important role in first-pass metabolism of low p.o. doses of SAM. In contrast to previous results in the normal dog, the p.o. coadministration of sodium sulfate did not reduce the bioavailability of SAM in transposed dogs. This indicates that the nonlinear intestinal first-pass metabolism of SAM is not due to the depletion of the cosubstrate precursor, inorganic sulfate.