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 was used as a model drug to test the hypothesis that fetal metabolism contributes significantly to drug clearance by the fetus. Infusions of morphine, morphine-3-β-glucuronide (M3G), and morphine-6-β-glucuronide (M6G) were administered to the fetal baboon. Plasma concentrations of drug and metabolite obtained near steady state were measured by high-performance liquid chromatography. During morphine infusion, morphine, M3G, and M6G concentrations rose linearly with dose. M3G concentrations exceeded M6G by 20-fold. Mean ± S.D. 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 seemed to be dose-independent. The mean ± S.D. 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 with in vitro estimates of metabolism and morphine clearance in human infants. For morphine, fetal drug metabolism accounts for half the difference between fetal and maternal plasma concentrations.
Footnotes
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This research was supported by the National Institute of Drug Abuse and the Aaron Diamond Foundation. Dr. Garland was a recipient of an Aaron Diamond Postdoctoral Research Fellow.
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This research was initially presented at the Pediatric Academic Societies' Annual Meeting (2000 May 12-16, Boston, MA; 2001 Apr 28-May 1, Baltimore, MD): Garland M, Abildskov K, Daniel SS, Myers MM, Szeto HH, and Stark RI (2000) Saturation kinetics of morphine glucuronidation in the fetal baboon. Pediatr Res (Part 2; Suppl S): ; and Garland M, Abildskov K, Daniel SS, and Stark RI (2001) Quantification of morphine metabolism by the fetal baboon. Pediatr Res (Part 2; Suppl S): .
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doi:10.1124/dmd.104.001388.
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ABBREVIATIONS: UGT, UDP-glucuronosyltransferase; M3G, morphine-3-β-glucuronide; M6G, morphine-6-β-glucuronide; GA, gestational age; HPLC, high-performance liquid chromatography.
- Received July 8, 2004.
- Accepted October 14, 2004.
- The American Society for Pharmacology and Experimental Therapeutics
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