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A Rane, J Sawe, B Lindberg, JO Svensson, M Garle, R Erwald and H Jorulf
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 3.15 l X kg b.wt.-1. The systemic blood clearance (9.2-21.3 ml X min-1 X kg b.wt.-1) was in the same range as the estimated hepatic blood clearance (9.7-23.9 ml X min-1 X kg b.wt.-1). After i.v. administration, the blood concentrations of morphine-3-glucuronide ( M3G ) were 8 to 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 metabolite levels in blood was similar to the relative formation rates for M3G and morphine-6-glucuronide in liver microsomal preparations (less than .039). The intrinsic hepatic metabolic clearance of morphine as estimated from the apparent enzyme kinetic constants Vmax 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, however, underestimates of the experimentally determined hepatic extraction ratio, which varied between 0.61 and 0.74. This indicates that 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 it has been shown previously that such prediction from in vitro data is possible.
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