pgp - publications

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1. Yakugaku Zasshi. 2012;132(2):161-6.

Altered Intestinal P-glycoprotein Expression Levels Affect Pharmacodynamics under
Diabetic Condition.

Nawa A, Fujita-Hamabe W, Kisioka S, Tokuyama S.

Department of Clinical Pharmacy, School of Pharmaceutical Sciences, Kobe Gakuin

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

PMID: 22293693 [PubMed - in process]