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Accumulation and clearance of morphine-3-beta-D-glucuronide in fetal lambs
G D Olsen1, K M Sommer, P L Wheeler
1Department of Pharmacology, School of Medicine, Oregon Health Sciences University, Portland.
Abstract:
The time course and extent of morphine-3-beta-D-glucuronide (M3G) production from morphine (MOR) and the clearance of M3G from plasma was studied in the late gestation fetal lamb. MOR was infused at a constant rate into the fetal vena cava and plasma was sampled from the fetus and ewe. Amniotic fluid was also sampled in one animal. M3G was produced in the fetal lamb and accumulated extensively in fetal plasma and amniotic fluid. Seizure activity was observed in two fetal lambs with extremely high plasma concentrations of M3G and MOR. The molar ratio of M3G to MOR in fetal plasma was dependent upon the duration of infusion, reaching a plateau of 60 at about 3 days, but appeared to be independent of the infusion rate over the range studied, 3 to 30 mg hr-1. Maternal plasma MOR and M3G concentrations were substantially less than corresponding fetal plasma concentrations. Using the steady-state plasma concentration of M3G obtained from infusion of MOR and the clearance of M3G derived from single injection of M3G to fetal lambs, the fraction of MOR converted to M3G by the fetus was calculated to be 0.63. Although MOR is conjugated to glucuronic acid in the fetal lamb and excreted into the amniotic fluid it is not readily transferred across the epitheliochorial placenta to the ewe because of restricted permeability.
Insights
Morphine-3-glucuronide (M3G) is extensively produced and accumulates in fetal lambs, with high concentrations linked to seizures. The fetus converts a significant portion of morphine (MOR) to M3G, which is poorly transferred to the mother.
Area of Science:
- Pharmacology
- Developmental Biology
- Toxicology
Background:
- Morphine (MOR) metabolism and its principal metabolite, morphine-3-glucuronide (M3G), are critical in understanding neonatal opioid exposure.
- Limited data exists on M3G production and clearance dynamics in the late-gestation fetus.
Purpose of the Study:
- To investigate the time course and extent of M3G production from MOR.
- To determine M3G clearance from fetal plasma.
- To assess the relationship between M3G/MOR concentrations and potential adverse effects like seizures.
Main Methods:
- Constant infusion of MOR into the fetal lamb vena cava.
- Serial plasma sampling from fetus and ewe, and amniotic fluid sampling.
- Single injection of M3G to determine fetal M3G clearance.
Main Results:
- M3G was extensively produced and accumulated in fetal plasma and amniotic fluid.
- Seizure activity observed in fetuses with extremely high M3G and MOR plasma concentrations.
- Molar ratio of M3G to MOR reached a plateau of 60; maternal concentrations were significantly lower than fetal.
- Calculated fetal MOR conversion to M3G was 0.63.
Conclusions:
- The late-gestation fetal lamb extensively conjugates MOR to M3G, leading to high fetal M3G accumulation.
- High M3G concentrations are associated with adverse neurological effects (seizures) in fetal lambs.
- Restricted placental transfer limits M3G and MOR transfer to the ewe, highlighting fetal vulnerability.