The effect of halothane on morphine disposition: relative contributions of the liver and kidney to morphine glucuronidation in the dog.

The present study determined the effect of halothane on the disposition of morphine by defining the effect of halothane anesthesia on the systemic, renal, and hepatic clearance of the parent compound, morphine, and on the generation of the primary metabolite, morphine-3-glucuronide (M3G) in the dog. Unlabeled morphine, 3H-morphine, and 14C-morphine were simultaneously administered into the portal vein, femoral vein, and renal artery, respectively, first during pentobarbital anesthesia and second during halothane (1.5 MAC) anesthesia; blood samples were taken for estimation of unlabeled plasma morphine and M3G concentrations by high performance liquid chromatography (HPLC). 3H- and 14C-morphine concentrations and corresponding M3G concentrations were determined by dual-channel liquid scintillation counting of the eluant corresponding to the appropriate peak on the HPLC. The portal clearance of morphine was not altered by halothane. However, intravenous (iv) morphine clearance (CLs) decreased (P less than 0.05) by 40% from 963 +/- 131 to 579 +/- 91 ml/min during halothane anesthesia, accompanied by an increase (P less than 0.05) in half-life from 78 +/- 8 to 106 +/- 8 min. The reduction in CLs of morphine occurred putatively on the basis of a halothane-induced decrease in hepatic blood flow, whereas morphine metabolism, reflected by morphine portal (intrinsic) clearance, was not significantly decreased by halothane. There was no significant effect of halothane on the partial metabolic clearance of morphine to M3G, and the ratio of area under the plasma concentration-time curve (AUC)-M3G to AUC unchanged morphine was not significantly altered by halothane, indicating that morphine glucuronidation is unaffected by halothane anesthesia.(ABSTRACT TRUNCATED AT 250 WORDS)