Abstract
The effect of phenylbutazone on the disposition of (S)-acenocoumarol in the rat was studied at steady state conditions of distribution and elimination. (S)-Acenocoumarol was administered by constant rate infusions (1 microgram/min). The biliary excretion of 6- and 7-hydroxylated acenocoumarol was followed and the intrahepatic distribution was investigated. Phenylbutazone (50 mg/kg) increased the plasma unbound fraction about 4-fold. (S)-Acenocoumarol plasma clearance was enhanced (2.8 +/- 0.15 vs. 1.54 +/- 0.14 ml/min) but the unbound plasma clearance was reduced by 50% (67 +/- 9 vs. 140 +/- 27 ml/min). Phenylbutazone caused an intrahepatic redistribution of (S)-acenocoumarol, i.e. the drug shifted from the cytosol to the 10,000g pellet. The cytosolic unbound concentration, however, was increased. The (S)-acenocoumarol content in the microsomal fraction was not affected. The biliary excretion rate of total metabolite (free plus conjugated) comprised 50% of the (S)-acenocoumarol infusion rate in controls and was slightly stimulated (+20%) by phenylbutazone. The biliary excretion of free metabolites, however, was greatly increased (62 +/- 7 vs. 22 +/- 6 ng/min for 6-hydroxy-acenocoumarol; 337 +/- 38 vs. 141 +/- 32 ng/min for 7-hydroxy-acenocoumarol). This effect is probably due to stimulation of a hepatic biliary transport system; the rate constant for transport of 7-hydroxy-acenocoumarol was enhanced 5-fold (0.107 +/- 0.03 vs. 0.021 +/- 0.007 min-1).
DMD articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|