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Glucuronidation of morphine in human kidney microsomes
Q Y Yue1, I Odar-Cederlöf, J O Svensson
1Department of Clinical Pharmacology, Huddinge University Hospital, Sweden.
Abstract:
The UDP-glucuronyltransferase (GT) activity with morphine as substrate was measured in microsomes prepared from seven human adult kidneys including one whose cortex and medulla had been separated. The formation of morphine-3- and 6-glucuronides (M3G and M6G) was determined by HPLC methods. All kidney specimen formed M3G and M6G when incubated with morphine and UDP-glucuronic acid (UDPGA). The estimated Vmax and Km of morphine to form M3G and M6G were 2.2 and 0.18 nmol per mg protein and min. and 8.2 and 4.6 mM, respectively. The corresponding values for UDPGA were 1.3 and 0.13 nmol per mg protein and min. and 5.4 and 4.1 mM, respectively. The GT activity in cortex was 2.8-fold higher than in the medulla. The human kidney thus contains glucuronyltransferase activities towards morphine, which is in contrast to previous findings in the rat.
Insights
Human kidneys exhibit UDP-glucuronyltransferase (GT) activity, metabolizing morphine into glucuronides. This kidney GT activity differs from findings in rats, with higher activity observed in the renal cortex compared to the medulla.
Area of Science:
- Pharmacology
- Biochemistry
- Nephrology
Background:
- Morphine metabolism is crucial for its efficacy and toxicity.
- UDP-glucuronyltransferase (GT) enzymes play a key role in drug conjugation.
- Previous studies suggested limited morphine glucuronidation in rat kidneys.
Purpose of the Study:
- To investigate UDP-glucuronyltransferase (GT) activity in human kidneys using morphine as a substrate.
- To quantify the formation of morphine glucuronides (M3G and M6G) in human kidney microsomes.
- To compare GT activity between human kidney cortex and medulla.
Main Methods:
- Human adult kidney microsomes were prepared from seven specimens.
- Morphine glucuronidation (M3G and M6G) was measured using High-Performance Liquid Chromatography (HPLC).
- Kinetic parameters (Vmax and Km) for morphine and UDP-glucuronic acid (UDPGA) were determined.
Main Results:
- All human kidney samples demonstrated the ability to form M3G and M6G from morphine and UDPGA.
- Specific kinetic parameters (Vmax and Km) for morphine and UDPGA were quantified.
- UDP-glucuronyltransferase (GT) activity was significantly higher in the kidney cortex (2.8-fold) than in the medulla.
Conclusions:
- Human kidneys possess significant UDP-glucuronyltransferase (GT) activity towards morphine.
- The human kidney's capacity for morphine glucuronidation contrasts with prior findings in rat kidneys.
- Renal cortex exhibits a higher metabolic capacity for morphine glucuronidation compared to the medulla.