Induction of Hepatic Drug-Metabolizing Enzymes by Propoxyphene

Abstract

Pretreatment of mice with propoxyphene napsylate (PN, 200 mg/kg,PO, twice daily for 5 days) shortened hexobarbital sleeping time without affecting the brain barbiturate concentrations. It also produced an increase in liver weight, microsomal protein, hepatic microsomal cytochrome P-450 content and aminopyrine N-demethylase activity. These increases were prevented by simultaneous administration of actinomycin D (200 μg/kg,IP) or puromycin dihydrochloride (80 mg/kg,IP). The inductive effect was found to be dose-dependent up to 200-250 mg/kg; at higher doses the effect was less apparent. The effect reached its maximum in 3 days and then regressed to normal in about 4 days after cessation of the drug. Kinetic studies provided support for the concept that the enzymes from both normal and PN-treated livers were the same. However, this dosage schedule of PN had no effect on aniline hydroxylase activity except at a maximum inductive dose of 200 mg/kg, PO. When examined under an electron microscope, PN could cause proliferation of the smooth endoplasmic reticulum of the hepatocytes as well as a high degree of accumulation of lipid droplets. All of these findings thus suggest that the narcotic analgesic when given subacutely may not only possess several microsomal inductive properties similar to phenobarbital but also a certain degree of hepatotoxicity.

Propoxyphene is a common analgesic drug widely used throughout the world. Its use, however, is frequently associated with suicide and accidental deaths, especially when taken in conjunction with other drugs(1-3). Severe propoxyphene intoxication is associated with rapid onset of generalized central nervous system depression, respiratory depression, cardiotoxicity and convulsions (3-5). Recently, Peterson et al (6) have found that propoxyphene when given acutely can behave as a potent inhibitor of hepatic microsomal mixed-function oxidases, acting in a manner similar to SKF 525-A. This finding thus provides evidence that deaths related to propoxyphene overdose could be a consequence of pharmacokinetic drug interactions in which propoxyphene or its metabolites, by inhibiting the metabolism of other drugs, may produce more profound toxic effects than those due to the sum of the pharmacodynamic effects of the ingested drugs. Furthermore, these investigators (6) have also reported that chronic administration of propoxyphene could increase the rate of its own metabolism as well as that of aminopyrine and aniline, thus suggesting the drug as an enzyme inducer.

In this communication, the inductive effects of propoxyphene on mouse microsomal drug-metabolizing enzymes and liver cell morphology are described. Evidence is presented to suggest that this analgesic when given subacutely possesses a number of microsomal inductive properties similar to phenobarbital as well as a certain degree of hepatotoxicity.