title: [Altered intestinal P-glycoprotein expression levels affect pharmacodynamics under diabetic condition].
abstract: P-glycoprotein (P-gp), one of the important drug-efflux pumps, is known to affect pharmacokinetics and pharmacodynamics of P-gp substrate drugs. We have previously reported that intestinal P-gp expression levels are transiently decreased in streptozotocin (STZ)-induced type 1 diabetic mouse model. Herein, we examined the analgesic effects of orally administered morphine and its pharmacokinetic properties under diabetic conditions, specifically focusing on the involvement of intestinal P-gp in a type 1 diabetic mouse model. Type 1 diabetes was induced in male ddY mice by an i.p. injection of STZ (230 mg/kg). We assessed the oral morphine analgesia using the tail-flick test. Serum and brain morphine content were determined on a HPLC-ECD system. Intestinal P-gp expression levels were significantly decreased on day 9 after STZ administration. On the other hands, oral morphine analgesia, and serum and brain morphine content were significantly increased on day 9 after STZ administration. The decrease in the intestinal P-gp expression levels were suppressed by aminoguanidine, a specific iNOS inhibitor. Interestingly, the increase in the analgesic effect of morphine, as well as serum and brain morphine content, was suppressed by aminoguanidine. Conversely, there was no change in the analgesic effect obtained with subcutaneous morphine in STZ-treated mice. In conclusions, our findings suggest that the oral morphine analgesia is dependent on intestinal P-gp expression, and that may be one of the problems against obtaining stable pharmacological effects of morphine in diabetic patients.
authors.affiliation: Department of Clinical Pharmacy, School of Pharmaceutical Sciences, Kobe Gakuin University, Kobe, Japan.
authors.forename: Ayaka
authors.initials: A
authors.lastname: Nawa
authors.forename: Wakako
authors.initials: W
authors.lastname: Fujita-Hamabe
authors.forename: Shiroh
authors.initials: S
authors.lastname: Kisioka
authors.forename: Shogo
authors.initials: S
authors.lastname: Tokuyama
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism* / Q000502:physiology*; D060433:Administration, Ophthalmic; D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006146:Guanidines / Q000494:pharmacology; D007413:Intestinal Mucosa / Q000378:metabolism*; D008297:Male; D051379:Mice; D009020:Morphine / Q000008:administration & dosage / Q000493:pharmacokinetics*; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors; D013997:Time Factors; D014018:Tissue Distribution
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000701:Analgesics, Opioid; D004791:Enzyme Inhibitors; D006146:Guanidines; D009020:Morphine; D052247:Nitric Oxide Synthase Type II; C004479:pimagedine