title: 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.
abstract: 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.
authors.affiliation: Faculty of Pharmaceutical Sciences, Kobe Gakuin University, Chuo-ku, Kobe, Japan.
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Hasegawa
authors.forename: Shuichi
authors.initials: S
authors.lastname: Kishimoto
authors.forename: Naoki
authors.initials: N
authors.lastname: Shibatani
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Nomura
authors.forename: Yuko
authors.initials: Y
authors.lastname: Ishii
authors.forename: Mika
authors.initials: M
authors.lastname: Onishi
authors.forename: Nobuo
authors.initials: N
authors.lastname: Inotsume
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Takeuchi
authors.forename: Shoji
authors.initials: S
authors.lastname: Fukushima
mesh_terms: 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
chemical_list: 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