Development of tolerance to the inhibitory effect of loperamide on gastrointestinal transit in mice.

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Tan-No K, Niijima F, Nakagawasai O, Sato T, Satoh S, Tadano T

Development of tolerance to the inhibitory effect of loperamide on gastrointestinal transit in mice.

Eur J Pharm Sci. 2003 Nov;20(3):357-63.

PubMed ID

14592702 [ View in PubMed

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Abstract

The inhibitory effect of repetitiously administered loperamide, a peripheral mu-opioid receptor agonist and well-recognized antidiarrheal agent, on mouse gastrointestinal transit was compared with that of morphine in order to examine the development of tolerance to mu-opioid receptor agonist-induced constipation (antitransit effect). When administered subcutaneously 15 min before the oral injection of charcoal meal, loperamide (0.1-30 mg/kg) and morphine (1-8 mg/kg) dose-dependently and significantly inhibited gastrointestinal transit of charcoal with the ID(50) values of 1.6 (0.3-7.1) mg/kg and 3.6 (1.5-8.5) mg/kg, respectively. When loperamide (30 mg/kg) was administered twice daily for 2 days, the antitransit effect was significantly reduced. On the other hand, morphine did not develop tolerance in even more severe conditions than those of loperamide. It is known that P-glycoprotein, an ATP-dependent drug efflux pump, is involved in the development of tolerance to morphine analgesia. The tolerance observed with loperamide was significantly prevented by cyclosporin (30 mg/kg, i.p.), a P-glycoprotein inhibitor, thus the ID(50) value in loperamide-tolerant mice was markedly reduced from >1000 mg/kg to 40 (2.7-603.0) mg/kg by cyclosporin. These results indicate that loperamide, different from morphine, readily develops tolerance to the inhibitory effect on mouse gastrointestinal transit, and the P-glycoprotein may be involved in the development of tolerance to the antitransit effect of loperamide.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Loperamide	Mu-type opioid receptor	Protein	Humans	Yes	Agonist	Details