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J Pharm Pharmacol. 2009 Sep;61(9):1205-10. doi: 10.1211/jpp/61.09.0010.

Altered expression of MRP2, MRP3 and UGT2B1 in the liver affects the disposition of morphine and its glucuronide conjugate in a rat model of cholestasis.

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1
Laboratory of Clinical Pharmaceutics, Kobe Gakuin University, Kobe 650-8586, Japan.

Abstract

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.

PMID:
19703370
DOI:
10.1211/jpp/61.09.0010
[Indexed for MEDLINE]

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