THE DISPOSITION OF MORPHINE AND ITS METABOLITES IN THE IN-SITU RAT ISOLATED-PERFUSED LIVER

A specific HPLC method with UV detection was used to investigate the d isposition of morphine and its metabolites in the in-situ rat isolated perfused liver preparation. Livers of male Sprague-Dawley rats (n = 4 ) were perfused under single pass conditions with protein- and erythro cyte-free perfusate, containing 2.66 mu M morphine, for up to 90 min. The concentration of morphine, normorphine and morphine-3-glucuronide (M3G) in outflow perfusate, and the biliary excretion of M3G and normo rphine glucuronide, all reached steady-state levels within 15-20 min a fter commencing perfusion. At steady-state, the mean (+/- s.d.) extrac tion ratio of morphine was 0.87 +/- 0.06 and clearance (26.0 +/- 1.7 m L min(-1)) approached perfusate flow rate (30 mL min(-1)). Although M3 G was the main metabolite, accounting for 72.8 +/- 12.7% of eliminated morphine, a significant proportion (21.6 +/- 13.5%) was N-demethylate d to normorphine and was recovered as unchanged normorphine in outflow perfusate and normorphine glucuronide in bile. The biliary extraction ratio of hepatically-formed M3G was 0.61 +/- 0.31. Results from an ad ditional six experiments, in which livers were perfused with 1.33 and 2.66 mu M of morphine for 30 min each in a balanced cross-over manner, indicated that the disposition of morphine and its metabolites was ap proximately linear within this concentration range.