The pharmacokinetics of morphine and its glucuronide conjugate in a rat model of streptozotocin-induced diabetes and the expression of MRP2, MRP3 and UGT2B1 in the liver.
OBJECTIVE
The aim was to investigate the pharmacokinetics of morphine and its metabolite, morphine-3-glucuronide (M3G), in a rat model of streptozotocin (STZ)-induced diabetes.


METHODS
Morphine (15 mg/kg) was administered intravenously, and the concentrations of morphine and M3G in the plasma, urine and bile were measured by HPLC. Changes in the expression of multidrug resistance-associated proteins (MRP2 and MRP3) and UDP-glucuronosyltransferase 2B1 (UGT2B1) mRNA in the liver were also estimated by reverse-transcriptase PCR.


RESULTS
Plasma morphine concentrations were lower in the STZ-diabetic rats than controls although the elimination half-life of morphine was similar in the two groups (47.9 +/- 10.7 min and 47.2 +/- 8.6 min, respectively). The concentration of M3G in plasma was higher in STZ-diabetic than control rats, and the biliary excretion of M3G was lower in the STZ-diabetic rats (7.4 +/- 2.3% vs 13.3 +/- 2.0%). The urinary excretion of M3G was similar in the two groups (10.1 +/- 6.8% vs 10.9 +/- 4.9%). The expression of MRP3 and UGT2B1 mRNA was increased in STZ-diabetic rats, whereas expression of MRP2 mRNA was decreased.


CONCLUSIONS
In STZ-diabetic rats, the distribution volume of morphine increased, the glucuronidation rate and M3G transportation into the blood were enhanced, and the excretion of M3G was decreased, leading to an increase in the plasma M3G concentration.
Hasegawa
Yoshitaka
Y
Faculty of Pharmaceutical Sciences, Kobe Gakuin University, Chuo-ku, Kobe, Japan.
Kishimoto
Shuichi
S
Shibatani
Naoki
N
Nomura
Hiromichi
H
Ishii
Yuko
Y
Onishi
Mika
M
Inotsume
Nobuo
N
Takeuchi
Yoshikazu
Y
Fukushima
Shoji
S
D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000701:Analgesics, Opioid / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D001646:Bile / Q000378:metabolism; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D014453:Glucuronosyltransferase / Q000235:genetics / Q000378:metabolism*; D006207:Half-Life; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D009020:Morphine / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology*; D009022:Morphine Derivatives / Q000097:blood / Q000378:metabolism* / Q000652:urine; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017450:Receptors, Opioid, mu / Q000819:agonists; D020133:Reverse Transcriptase Polymerase Chain Reaction
D018528:ATP-Binding Cassette Transporters; D000701:Analgesics, Opioid; D014453:Glucuronosyltransferase; D009020:Morphine; D009022:Morphine Derivatives; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D012333:RNA, Messenger; D017450:Receptors, Opioid, mu; C423013:Abcc2 protein, rat; C114462:multidrug resistance-associated protein 3; C018108:morphine-3-glucuronide