PHARMACOKINETIC STUDIES OF PROPOXYPHENE .6. ACUTE EFFECT OF ETHANOL ON HEPATIC 1ST-PASS ELIMINATION OF PROPOXYPHENE IN RATS

  • 1 January 1981
    • journal article
    • research article
    • Vol. 219  (1) , 7-13
Abstract
Whether ethanol enhanced the acute toxicity of propoxyphene not only by its CNS depressant effect but by inhibiting the presystemic biotransformation of the analgesic was studied. Administration of propoxyphene to adult male rats by injection into the systemic (jugular vein) or hepatic portal circulation (pyloric vein) revealed that 40 .+-. 12% (mean .+-. SD) of a 12 mg/kg dose reached the systemic circulation intact after injection of the drug into the portal circulation. This estimate, based on the area under the plasma concentration time curve, was confirmed by the relative amounts of propoxyphene excreted unchanged in the urine. Acute infusions of ethanol, 1.5 ml/kg per h from -3 to 0 h and 0.5 ml/kg per h from 0 to +3 h into the portal circulation, increased total systemic clearance of propoxyphene from 64 to 95 ml/min per kg on the average (P < 0.02), probably due to increased hepatic blood perfusion rate. The same rate and route of ethanol administration caused an increase in the average systemic availablity of propoxyphene from 28 to 56% (P < 0.001) after injection of 8 mg/kg into the portal circulation. Since orally administered propoxyphene is ordinarily subject to extensive presystemic biotransformation in humans, the frequent association of ethanol intake with fatal propoxyphene intoxication may be due, at least in part, to an increased systemic availability of propoxyphene when taken with ethanol.