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Ethylmorphine metabolism in isolated rat hepatocytes
1National Institute of Forensic Toxicology, Oslo, Norway.
Pharmacology & Toxicology
|July 1, 1993
Summary
Ethylmorphine metabolism in rat hepatocytes yields morphine and norethylmorphine, which are further metabolized to glucuronides. Drug concentrations accumulate significantly within liver cells compared to the surrounding medium.
Area of Science:
- Pharmacology
- Hepatology
- Drug Metabolism
Background:
- Ethylmorphine is a substrate for hepatic metabolism.
- Understanding drug disposition in hepatocytes is crucial for predicting in vivo pharmacokinetics.
Purpose of the Study:
- To investigate the metabolic pathways of ethylmorphine in isolated rat hepatocytes.
- To quantify the formation of ethylmorphine metabolites and their intracellular accumulation.
Main Methods:
- Incubation of isolated rat hepatocytes with ethylmorphine.
- Analysis of ethylmorphine and its metabolites (morphine, norethylmorphine, normorphine, glucuronides) using chromatography.
- Measurement of intra- and extracellular drug concentrations.
Main Results:
- Ethylmorphine undergoes N- and O-dealkylation to morphine and norethylmorphine, respectively.
- Morphine and normorphine are glucuronidated, forming major end products: morphine-3-glucuronide and normorphine-3-glucuronide.
- Significant intracellular accumulation of ethylmorphine and its metabolites was observed, with concentration gradients across the hepatocyte membrane.
Conclusions:
- Rat hepatocytes metabolize ethylmorphine through dealkylation and glucuronidation.
- The formation of morphine-3-glucuronide is concentration-dependent.
- Hepatocytes actively transport and/or retain ethylmorphine and its metabolites, leading to substantial intracellular drug concentrations.