OBJECTIVES: The aim was to investigate the disposition of morphine and morphine-3-glucuronide (M3G) in a rat model of cholestasis induced by bile duct ligation (BDL). METHODS: Morphine (15 mg/kg) was administered intravenously, and morphine and M3G concentrations in the plasma and urine measured by HPLC. Changes in the mRNA expression of multidrug resistance-associated protein (MRP)2, MRP3 and UDP-glucuronosyltransferase (UGT)2B1 in the liver were estimated using RT-PCR. KEY FINDINGS: Although the plasma morphine concentrations declined exponentially, the elimination was delayed 3 and 5 days after BDL. Plasma M3G concentrations on day 1 after BDL were similar to those in the untreated control group, but were increased 3 and 5 days after BDL. Expression of MRP3 and UGT2B1 mRNA increased after BDL. The urinary excretion of M3G was increased significantly after BDL. CONCLUSIONS: Enhanced glucuronidation of morphine and transportation of M3G into the blood increased the plasma M3G concentration in the BDL groups. However, M3G disposition 1 day after BDL was similar to that in the untreated control group because urinary excretion of M3G increased.
OBJECTIVES: The aim was to investigate the disposition of morphine and morphine-3-glucuronide (M3G) in a rat model of cholestasis induced by bile duct ligation (BDL). METHODS:Morphine (15 mg/kg) was administered intravenously, and morphine and M3G concentrations in the plasma and urine measured by HPLC. Changes in the mRNA expression of multidrug resistance-associated protein (MRP)2, MRP3 and UDP-glucuronosyltransferase (UGT)2B1 in the liver were estimated using RT-PCR. KEY FINDINGS: Although the plasma morphine concentrations declined exponentially, the elimination was delayed 3 and 5 days after BDL. Plasma M3G concentrations on day 1 after BDL were similar to those in the untreated control group, but were increased 3 and 5 days after BDL. Expression of MRP3 and UGT2B1 mRNA increased after BDL. The urinary excretion of M3G was increased significantly after BDL. CONCLUSIONS: Enhanced glucuronidation of morphine and transportation of M3G into the blood increased the plasma M3G concentration in the BDL groups. However, M3G disposition 1 day after BDL was similar to that in the untreated control group because urinary excretion of M3G increased.
Authors: Anika L Dzierlenga; John D Clarke; Tiffanie L Hargraves; Garrett R Ainslie; Todd W Vanderah; Mary F Paine; Nathan J Cherrington Journal: J Pharmacol Exp Ther Date: 2014-12-15 Impact factor: 4.030