MORPHINE GLUCURONIDATION IN THE RHESUS-MONKEY - A COMPARATIVE INVIVO AND INVITRO STUDY

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  • 1 January 1984
    • journal article
    • research article
    • Vol. 229  (2) , 571-576
Abstract
The kinetics of morphine in the rhesus monkey after i.v. or oral administration including the hepatic extraction ratio determined directly in the portal and hepatic veins were compared with the glucuronidation of morphine in liver microsomes from the same animals. The plasma half-lives varied between 102 and 202 min, and the apparent volume of distribution was 2.68 to 3.151/kg bwt [body wt]. The systemic blood clearance (9.2-21.3 ml/min kg bwt) was in the same range as the estimated hepatic blood clearance (9.7-23.9 ml/min per kg bwt). After i.v. administration, the blood concentrations of morphine-3-glucuronide (M3G) were 8-11 times higher than those of morphine. The molar blood concentration ratio between morphine-6-glucuronide and M3G was 0.04 or less. The ratio between the metabolic levels in blood was similar to the relative formation rates for M3G and morphine-6-glucuronide in liver microsomal preparations (< 0.039). The intrinsic hepatic metabolic clearance of morphine as estimated from the apparent enzyme kinetic constants Vmax [maximum metabolic rate] and Km for the formation of the major M3G metabolite was used to predict the hepatic extraction ratio. The predicted values of the hepatic extraction ratio (0.09-0.14) were underestimates of the experimentally determined hepatic extraction ratio, which varied between 0.61 and 0.74. Evidently, unknown factors in the liver microsomal glucuronidation preclude the use of enzyme kinetics parameters obtained in vitro for the prediction of the hepatic extraction ratio of morphine. For some drugs that are oxidized, such prediction from in vitro data is possible.