Absorption and Distribution of Naloxone in Rats after Oral and Intravenous Administration

The effect of route of administration on the absorption and distribution of naloxone, a narcotic antagonist, was investigated in rats. Plasma levels were determined by GLC. Five minutes after intravenous administration of 1 mg./kg., the plasma concentration was 258 ng./ml. Plasma levels after low oral doses were undetectable; but after 100 mg./kg. orally, the peak level of unchanged drug was almost 5000 ng./ml. In terms of percent of administered dose, the maximum amount of naloxone in the calculated plasma volume is 1.04% of the intravenous dose versus 0.19% of the oral dose. Pharmacokinetic parameters were generated with a computer program; the models constructed are of a rapidly absorbed and rapidly excreted and/or metabolized drug. These results, together with results from absorption studies with ligated intestinal loops, indicate that poor absorption of naloxone is not the cause of its relatively low oral potency. In vitro metabolic studies with rat liver slices confirmed rapid naloxone metabolism, suggesting that the lower potency of oral naloxone compared to parenteral naloxone is due to rapid first-pass liver metabolism.