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.
OBJECTIVE
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.


RESULTS
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.
Hasegawa
Yoshitaka
Y
Laboratory of Clinical Pharmaceutics, Kobe Gakuin University, Kobe 650-8586, Japan.
Kishimoto
Shuichi
S
Takahashi
Hirokazu
H
Inotsume
Nobuo
N
Takeuchi
Yoshikazu
Y
Fukushima
Shoji
S
D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002779:Cholestasis / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D014453:Glucuronosyltransferase / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008297:Male; D009020:Morphine / Q000493:pharmacokinetics; D009022:Morphine Derivatives / Q000493:pharmacokinetics*; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism*; D009294:Narcotics / Q000493:pharmacokinetics*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D014158:Transcription, Genetic
D018528:ATP-Binding Cassette Transporters; D014453:Glucuronosyltransferase; D009020:Morphine; D009022:Morphine Derivatives; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009294:Narcotics; D012333:RNA, Messenger; C423013:Abcc2 protein, rat; C114462:multidrug resistance-associated protein 3; C018108:morphine-3-glucuronide