Received for publication July 20, 2004.
Revised October 14, 2004.
Accepted for publication October 14, 2004.

The contribution of fetal metabolism to the disposition of morphine

Abstract

The contribution of fetal metabolism to drug disposition in pregnancy is poorly understood. With maternal administration of morphine, like many drugs, steady-state concentrations in fetal plasma are less than in maternal plasma. The contribution of fetal metabolism to this difference is unknown. Morphine as a model drug was used to test the hypothesis that fetal metabolism contributes significantly to drug clearance by the fetus. Infusions of morphine, morphine-3--glucuronide (M3G) and morphine-6--glucuronide (M6G) were administered to the fetal baboon. Plasma concentrations of drug and metabolite obtained near steady-state were measured by HPLC. During morphine infusion, morphine, M3G and M6G concentrations rose linearly with dose. M3G concentrations exceeded M6G twenty-fold. Mean ± SD clearances of morphine, M3G and M6G from the fetus were 69 ± 17, 2.3 ± 0.60 and 1.6 ± 0.24 ml.min-1 respectively. Clearances appeared dose independent. The mean ± SD fraction of morphine dose metabolized was 32 ± 5.5 %. This converts to a fetal metabolic clearance of 22 ± 6.5 ml.min^-1. In conclusion, one third of the elimination of morphine from the fetal baboon is attributable to metabolism, one third to passive placental transfer, and one third undefined. Furthermore, there is no evidence for saturation of metabolism. Fetal metabolism is surprisingly high compared to in vitro estimates of metabolism and morphine clearance in human infants. For morphine, fetal drug metabolism accounts for half of the difference between fetal and maternal plasma concentrations.

Key words: developmental pharmacology, drug disposition, fetal drug metabolism, glucuronidation, HPLC, metabolite kinetics, pharmacokinetic modeling, pharmacokinetics

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