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

Hasegawa, Yoshitaka; Kishimoto, Seiji; Shibatani, Naoki; Nomura, Hiromichi; Ishii, Yuko; Onishi, Mika; Inotsume, Nobuo; Takeuchi, Yoshikazu; Fukushima, Shoji

doi:10.1211/jpp.62.03.0004

Cited by 33 publications

(21 citation statements)

References 13 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This is consistent with numerous earlier reports of a significant reduction in the antinociceptive potency of morphine that was associated with hyperglycemic state in diabetes [4,5,24]. Alteration in the µ-opioid receptor function, an increase in the levels of interleukin-1b, and accumulation of morphine-3-glucuronide were reported in diabetic rats [9]. Repeated (21 days) administration of venlafaxine (10 mg/kg, po) was reported to suppress mechanical hyperalgesia in STZ-induced diabetic rats, whereas a single administration of the drug reduced it only slightly.…”

supporting

confidence: 92%

“…The animals often display polyuria, diarrhea, and a gradual reduction in body weight. Some authors demonstrated that STZ treatment altered the expression of cytochromes P450 1A2, 2B1 and 4A in rat models of diabetes, which may induce changes in pharmacokinetics of experimental substances [9]. Diabetic rats exhibit many complications seen in patients with diabetic neuropathy, including hyperalgesia and progressive loss of sensory nerve conduction, impaired intraneuronal blood flow as well as micro-and macrovascular reactivity.…”

mentioning

confidence: 99%

See 1 more Smart Citation

165 Modification of Morphine Analgesia by Venlafaxine in Diabetic Neuropathic Pain Model

Cegielska-Perun¹,

Bujalska²,

Makulska-Nowak³

2010

Eur Journal of Pain Supp

View full text Add to dashboard Cite

Abstract:Background: The purpose of this study was to investigate the influence of single or chronic (21 days) administration of the serotonin and noradrenaline reuptake inhibitor, venlafaxine, on the antinociceptive action of the opioid receptor agonist, morphine, in streptozotocin (STZ)-induced hyperalgesia. Methods:The studies were performed on male Wistar rats. Changes in nociceptive thresholds were determined using mechanical stimuli. Diabetes was induced by a single administration of STZ (40 mg/kg, im). Results: Venlafaxine was shown to modulate analgesic activity of morphine in STZ-induced hyperalgesia. However, whereas acute co-administration of venlafaxine increased the analgesic activity of morphine, chronic treatment with venlafaxine attenuated opioid efficacy. Conclusion: Depending on the mode of administration (single or long-term), venlafaxine modulates analgesic activity of morphine. Further investigations are necessary to clarify the mechanisms of these interactions, which may be clinically relevant.

show abstract

supporting

confidence: 92%

mentioning

confidence: 99%

165 Modification of Morphine Analgesia by Venlafaxine in Diabetic Neuropathic Pain Model

Cegielska-Perun¹,

Bujalska²,

Makulska-Nowak³

2010

Eur Journal of Pain Supp

View full text Add to dashboard Cite

show abstract

“…Studying M6G activity in rodents is complicated, because although morphine is metabolized to both glucuronides by human UGT2B7, rodent Ugt2b1 metabolizes morphine exclusively to M3G (Kuo et al, 1991;Salem and Hope, 1997;Hasegawa et al, 2009). Nevertheless, hepatic-derived M3G and exogenously administered M6G are substrates for human and rodent MRP2/Mrp2 and MRP3/Mrp3, which are responsible for their hepatobiliary disposition (Zelcer et al, 2005;van de Wetering et al, 2007;Hasegawa et al, 2010). Biliary excretion, representing up to 20% of morphine glucuronide clearance (Garrett and Jackson, 1979;Ouellet and Pollack, 1995), is mediated by Mrp2.…”

Section: Introductionmentioning

confidence: 99%

“…Biliary excretion, representing up to 20% of morphine glucuronide clearance (Garrett and Jackson, 1979;Ouellet and Pollack, 1995), is mediated by Mrp2. Previous studies examined the pharmacokinetics of M3G in rats with streptozotocininduced diabetes and bile duct ligation-induced cholestasis (Hasegawa et al, 2009(Hasegawa et al, , 2010. Both disease states altered the expression of Ugt2b1, Mrp3, and Mrp2 and negatively affected the biliary excretion of M3G.…”

Section: Introductionmentioning

confidence: 99%

Mechanistic Basis of Altered Morphine Disposition in Nonalcoholic Steatohepatitis

Dzierlenga

Clarke

Hargraves

et al. 2014

J Pharmacol Exp Ther

View full text Add to dashboard Cite

Morphine is metabolized in humans to morphine-3-glucuronide (M3G) and the pharmacologically active morphine-6-glucuronide (M6G). The hepatobiliary disposition of both metabolites relies upon multidrug resistance-associated proteins Mrp3 and Mrp2, located on the sinusoidal and canalicular membrane, respectively. Nonalcoholic steatohepatitis (NASH), the severe stage of nonalcoholic fatty liver disease, alters xenobiotic metabolizing enzyme and transporter function. The purpose of this study was to determine whether NASH contributes to the large interindividual variability and postoperative adverse events associated with morphine therapy. Male Sprague-Dawley rats were fed a control diet or a methionine-and choline-deficient diet to induce NASH. Radiolabeled morphine (2.5 mg/kg, 30 mCi/kg) was administered intravenously, and plasma and bile (0-150 or 0-240 minutes), liver and kidney, and cumulative urine were analyzed for morphine and M3G. The antinociceptive response to M6G (5 mg/kg) was assessed (0-12 hours) after direct intraperitoneal administration since rats do not produce M6G. NASH caused a net decrease in morphine concentrations in the bile and plasma and a net increase in the M3G/morphine plasma area under the concentration-time curve ratio, consistent with upregulation of UDP-glucuronosyltransferase Ugt2b1. Despite increased systemic exposure to M3G, NASH resulted in decreased biliary excretion and hepatic accumulation of M3G. This shift toward systemic retention is consistent with the mislocalization of canalicular Mrp2 and increased expression of sinusoidal Mrp3 in NASH and may correlate to increased antinociception by M6G. Increased metabolism and altered transporter regulation in NASH provide a mechanistic basis for interindividual variability in morphine disposition that may lead to opioid-related toxicity.

show abstract

“…Hyperglycemia with DM affects not only the physiological condition of the patient but also often the pharmacokinetics of a drug; the non-enzymatic glycation of serum albumin was shown to influence the protein binding of certain drugs, which is one of the most important factors for the distribution of drugs doi: 10.7243/2053-7107-2-1 [13], and the activities/expressions of serum esterases and drug-metabolizing enzymes were also shown to be altered in DM [14,15]. These alterations have the ability to affect the pharmacokinetics of AS and DHA.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of efficacy and safety of artesunate and its active metabolite, dihydroartemisinin, in streptozotocin-induced diabetes rats by blood pharmacokinetic analysis

Fukushima¹,

Uchimura²,

Okada³

et al. 2014

Interact Med Chem

View full text Add to dashboard Cite

Background: Artesunate (AS), an anti-malarial drug, is hydrolyzed by serum esterase for its conversion to the active metabolite, dihydroartemisinin (DHA). Evidence for the clinical effectiveness of AS is growing; however, little information is available on special populations such as patients with diabetes mellitus (DM). In addition, although erythrocytes are considered as a target site, the blood pharmacokinetics of AS and DHA remain unclear. Therefore, the blood pharmacokinetics of AS and DHA were investigated in DM rats in the present study. Methods: DM rats were prepared by intraperitoneal injection of streptozotocin. An in vitro protein binding study of AS and DHA was performed by the ultrafiltration method. Plasma and blood samples were collected after the intravenous administration of AS, to analyze pharmacokinetics of AS and DHA. Blood to plasma ratios (BP ratio), as an index of erythrocyte distribution, were then calculated by dividing blood concentrations by plasma concentrations. Results: The protein bindings of AS and DHA were 83.7% and 92.6% in control rats and 86.2% and 92.2% in DM rats, respectively. All concentration profiles in this study were best fit by a two compartment model; the plasma and blood pharmacokinetic parameters of AS and DHA in DM rats were not significantly different from those in control rats. The BP ratio of AS was at an extremely low level (approximately 0.5) just after its administration, whereas that of DHA was maintained above 1.0 throughout the study; however, no significant changes were observed between control and DM rats. Conclusion:The glycation of albumin with DM did not affect the protein bindings of AS or DHA. No significant changes were observed in the conversion of AS to DHA by serum esterase or disposition of DHA in DM rats. The blood concentrations of DHA declined in parallel with plasma concentrations and the distribution of DHA to erythrocytes was good. In conclusion, the efficacy and safety of both AS and DHA were tolerated in DM rats with DHA having more favorable characteristics than AS.

show abstract

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: 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.

Cited by 33 publications

References 13 publications

165 Modification of Morphine Analgesia by Venlafaxine in Diabetic Neuropathic Pain Model

165 Modification of Morphine Analgesia by Venlafaxine in Diabetic Neuropathic Pain Model

Mechanistic Basis of Altered Morphine Disposition in Nonalcoholic Steatohepatitis

Evaluation of efficacy and safety of artesunate and its active metabolite, dihydroartemisinin, in streptozotocin-induced diabetes rats by blood pharmacokinetic analysis

Contact Info

Product

Resources

About