Abstract
The glucuronide metabolites of several widely used drugs are detected in fetal plasma after maternal drug administration. However, the disposition of these metabolites is poorly understood and clinical concerns have been raised about accumulation of active metabolites in the fetus. For this reason, morphine-3-β-glucuronide (M3G), an active metabolite of morphine, was studied to provide quantitative data on disposition. Maternal, fetal, and bidirectional placental clearances of M3G were measured in three pregnant baboons. During maternal infusion of M3G to steady-state, the glucuronide metabolite readily appeared in fetal plasma achieving a mean ± S.D. fetal-to-maternal concentration ratio of 0.79 ± 0.04. In paired maternal and fetal infusions, steady-state clearances were 53 ± 3 (maternal), 1.5 ± 0.5 (maternal-to-fetal), 2.6 ± 0.1 (fetal-to-maternal), and –0.70 ± 0.6 ml · min–1 (fetal). These clearance values support bidirectional transfer of M3G across the placenta and indicate negligible direct clearance from the fetus. The clearance of M3G across the placenta is more than 20-fold less than that of morphine. Despite this low index of permeability, placental transfer contributes significantly to the glucuronide pool in the fetus. Placental transfer emerges as the major clearance pathway for the glucuronide from the fetus and suggests a component of active efflux. What is more, the results do not support the concept of sequestration in the fetal intestine as a significant route of clearance. Together these results clarify the distribution and clearance of glucuronides in the pregnant primate and facilitate prediction of fetal exposure to active metabolites.
Footnotes
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This research was supported by the National Institute of Drug Abuse and National Institute of Child Health and Human Development.
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.108.021352.
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ABBREVIATIONS: M3G, morphine-3-β-glucuronide; M6G, morphine-6-β-glucuronide; HPLC, high-performance liquid chromatography; Cl, clearance; P1M, Model using data from paired infusions with single maternal compartment and single fetal compartment; P2M, Model using data from paired infusions with central and tissue maternal compartments and single fetal compartment; P2MNFC, Model using data from paired infusions with central and tissue maternal compartments and single fetal compartment with no direct fetal clearance; S1CPT, Model using data from single infusion with one compartment; S2CPT, Model using data from single infusion with central and tissue compartments; MRP, multidrug resistance-associated protein; BCRP, breast cancer resistance protein.
- Received March 4, 2008.
- Accepted June 17, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
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