Received for publication October 5, 2005.
Revised January 24, 2006.
Accepted for publication January 25, 2006.

Fetal morphine metabolism and clearance are constant during late gestation

Abstract

Fetal metabolism significantly contributes to the clearance of drugs from the fetus. To understand how the changes in fetal metabolism expected in late gestation alter fetal drug clearance, serial measurements of morphine metabolism were made in the fetal baboon over the latter third of gestation. Clearance and metabolism were evaluated in the context of fetal growth, onset of labor, and the administration of classical enzyme induction agents. Morphine, a probe substrate for the enzyme uridine diphosphate glucuronosyltransferase 2B7 (UGT2B7), was continuously infused to chronically catheterized fetal baboons while measuring morphine, morphine-3--glucuronide (M3G), and morphine-6--glucuronide (M6G) concentrations. In some animals, intermittent infusions of the metabolites provided estimates of metabolite clearance, and hence, the rate of formation of metabolites and metabolic clearance. Overall, metabolic clearance of morphine from the fetus was 27 ± 9.0 ml.min^-1 or 32% of total clearance. This is similar to the overall clearance in the adult baboon when standardized to weight. No change in any measure of metabolism or clearance of morphine or its glucuronide metabolites was found with gestational age, the presence of labor, or administration of UGT enzyme induction agents. Interpreting these findings using a physiologically based approach suggests that the intrinsic clearance of the fetal liver toward morphine is of sufficient magnitude that fetal hepatic clearance is flow limited. The implication of a high intrinsic clearance is for significant placento-hepatic first pass metabolism when drugs are administered to the mother. The previously held view of the "inadequacy of perinatal glucuronidation" needs to be reconsidered.

Key words: developmental pharmacology, drug clearance, drug disposition, fetal drug metabolism, HPLC, induction, metabolite kinetics, pharmacokinetics, phase II drug metabolism, UDP glucuronyltransferases

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