Phenylbutazone-hydroxycoumarol interactions. Effects on steady state disposition, hepatocellular distribution, and biliary excretion of (S)-acenocoumarol in rats.
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).
Thijssen
H H
HH
Department of Pharmacology, University of Limburg, Maastricht, The Netherlands.
Baars
L G
LG
Janssen
G M
GM
D000074:Acenocoumarol / Q000378:metabolism / Q000493:pharmacokinetics*; D000818:Animals; D001646:Bile / Q000187:drug effects / Q000378:metabolism*; D001711:Biotransformation; D001798:Blood Proteins / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008657:Metabolic Clearance Rate; D008862:Microsomes, Liver / Q000378:metabolism; D010653:Phenylbutazone / Q000494:pharmacology*; D011485:Protein Binding; D051381:Rats; D011919:Rats, Inbred Strains
D001798:Blood Proteins; D010653:Phenylbutazone; D000074:Acenocoumarol