THE EFFECT OF HALOTHANE ON MORPHINE DISPOSITION - RELATIVE CONTRIBUTIONS OF THE LIVER AND KIDNEY TO MORPHINE GLUCORONIDATION IN THE DOG

The present study determined the effect of halothane on the disposition of morphine by defining the effect of halothane anesthesia in 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 clearnace (CL(s)) decreased (P<0.05) by 40% from 963 ± 131 to 579 ± 91 ml/min during halothane anesthesia, accompanied by an increase (P<0.05) in half-life from 78 ± 8 to 106 ± 8 min. The reduction in CL(s) 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. Because controversy surrounds the role of the kidney in morphine metabolism, the relative contribution of the kidney and liver to morphine glucuronidation was also determined. The clearance of morphine following infusion into the renal artery (1,309 ± 258 ml/min) and femoral vein (979 ± 135 ml/min) was not significantly different (P = 0.46). In contrast, when morphine was given via the portal vein, its clearance (2,185 ± 558 ml/min) was significantly (P<0.05) greater than that following systemic administration, and the hepatic extraction ratio was 35 ± 11%. The extraction ratio of morphine across the kidney did not differ significantly from zero. The production of M3G as assessed by the ratio of AUC-M3G to the AUC for unchanged morphine was twofold higher (P<0.05) following intraportal administration than following either systemic or renal administration. There was no significant difference between the generation of M3G after intravenous (iv) and renal artery administration. Thus, there is little glucuronidation of morphine by the kidney in vivo.