Acute inhibition of microsomal drug metabolism by propoxyphene in narcotic tolerant/dependent mice

Propoxyphene (Darvon) was compared to SKF 525-A, a prototypical inhibitor of hepatic microsomal mixed function oxidases, to assess propoxyphene's potential to inhibit drug metabolism in morphine tolerant/dependent mice. $\text{In vitro}$, both propoxyphene (K_i = 3.5 × 10^?5M) and SKF 525-A (K_i = 4.3 × 10^?6M) inhibited the activity of aminopyrine N-demethylase competitively in hepatic microsomes from tolerant/dependent animals. Propoxyphene and SKF 525-A were weaker, noncompetitive inhibitors of aniline hydroxylase activity. $\text{In vivo}$, equimolar doses (0.24 mmoles/kg, i.p.) of each compound inhibited both of the above monooxygenases in the 10,000$\text{g}$ supernatant fractions of livers from the tolerant/ dependent animals. Propoxyphene was 40–50% as potent an inhibitor of these activities as SKF 525-A. A dose (300 mg/kg) of propoxyphene napsylate, shown to prevent narcotic abstinence signs with no observable toxicity in withdrawing mice, significantly prolonged the blood levels of injected pentobarbital and tripled pentobarbital sleeping time in these animals. When administered at 300 mg/kg chronically, propoxyphene napsylate acted as an inducer of its own metabolism. Propoxyphene napsylate, then, given acutely to narcotic tolerant/dependent mice, is a potent inhibitor of microsomal drug metabolizing capacity. Given chronically, it enhances this capability.