Effects of repeated morphine treatment on the antinociceptive effects, intestinal absorption, and efflux from intestinal epithelial cells of morphine.
The present study was conducted to investigate the effects of repeated treatment with morphine on the drug's antinociceptive effects, intestinal absorption, and transepithelial transport. The antinociceptive effects of morphine in rats were markedly decreased after repeated oral administration of the drug for 5 d, indicating the development of tolerance. In the morphine-tolerant rats, intestinal absorption of morphine was determined using the in situ loop method. Absorption of morphine from the jejunum was significantly decreased after repeated administration. The permeability of human intestinal epithelial Caco-2 cells was increased in the efflux direction after repeated treatment. The repeated administration of morphine also reduced the cellular accumulation and efflux of P-glycoprotein substrates ([(3)H]vincristine and rhodamine123) from Caco-2 cells, suggesting that it enhances P-glycoprotein-mediated efflux in Caco-2 cells. These results suggest that repeated use enhances the efflux of morphine in the epithelial cells of the small intestine, subsequently decreasing its intestinal absorption.
Okura
Takashi
T
Department of Pharmacokinetics, University of Shizuoka School of Pharmaceutical Sciences, Yada, Suruga-ku, Japan.
Ozawa
Tadahiro
T
Ibe
Michiko
M
Taki
Yuko
Y
Kimura
Midori
M
Kagawa
Yoshiyuki
Y
Kato
Yoshihisa
Y
Yamada
Shizuo
S
D000701:Analgesics, Opioid / Q000008:administration & dosage*; D000818:Animals; D018938:Caco-2 Cells; D002465:Cell Movement / Q000187:drug effects* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D006801:Humans; D007408:Intestinal Absorption / Q000187:drug effects* / Q000502:physiology; D007413:Intestinal Mucosa / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D007421:Intestine, Small / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009020:Morphine / Q000008:administration & dosage / Q000493:pharmacokinetics*; D010147:Pain Measurement / Q000187:drug effects* / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley
D000701:Analgesics, Opioid; D009020:Morphine