Abstract
The antitumor drug irinotecan clinically causes severe diarrhea as a side effect. Thromboxane A2 (TXA2), released by irinotecan, has been shown to be a novel physiological stimulant of Cl− secretion in the rat colon. Herein, we examined the effect of loperamide, an antidiarrhea drug, on Cl−secretion induced by irinotecan; 9,11-epithio-11,12-methano-thromboxane A2(STA2), a stable TXA2 analog; and prostaglandin E2 (PGE2) by using isolated mucosae of the rat colon. In the presence of atropine, loperamide in a concentration-dependent manner inhibited the Cl− secretion induced by irinotecan, STA2, and PGE2. However, the drug inhibited more effectively the irinotecan- and STA2-induced secretion (IC50 = 0.7 and 1.2 μM, respectively) than the PGE2-induced secretion (IC50 = 23 μM). Naloxone, an opiate antagonist, did not affect the antisecretory action of loperamide. Similar to the case for loperamide, W-7, a specific calmodulin antagonist, inhibited more effectively the STA2-induced Cl− secretion (IC50 = 5 μM) than the PGE2-induced secretion (IC50 = 36 μM). W-5, a low-affinity calmodulin antagonist (a dechlorinated control analog of W-7), also inhibited the STA2-induced secretion, but this effect was much less than that of W-7. STA2-induced increase in the intracellular free Ca2+ concentration of single colonic crypt cells was not affected by loperamide. We suggest that loperamide efficiently inhibits the TXA2-induced secretion by blocking the calmodulin system in the colonic epithelium. The present results may explain why coadministration of loperamide with irinotecan is clinically efficient for avoiding the irinotecan-induced side effect of diarrhea.
Footnotes
-
Send reprint requests to: Dr. Hideki Sakai, Department of Pharmaceutical Physiology, Faculty of Pharmaceutical Sciences, Toyama Medical and Pharmaceutical University, 2630 Sugitani, Toyama 930-0194, Japan. E-mail: sakaih{at}ms.toyama-mpu.ac.jp
-
↵1 This work was supported in part by grant-in-aid for Encouragement of Young Scientists from Japan Society for the Promotion of Science (to H.S.), grant-in-aid for Scientific Research (B) from the Ministry of Education, Science, Sports and Culture of Japan (to N.T.), and by grants from Suzuken Memorial Foundation and Takeda Science Foundation (to H.S.).
-
↵2 These authors contributed equally to this work.
-
↵3 Present address: Department of Environmental Biochemistry and Toxicology, University of Shizuoka School of Pharmaceutical Science, Shizuoka 422-8002, Japan.
- Abbreviations:
- TXA2
- thromboxane A2
- U46619
- 9,11-dideoxy-9α,11α-methanoepoxy prostaglandin F2α
- STA2
- 9,11-epithio-11,12-methano-thromboxane A2
- PGE2
- prostaglandin E2
- Isc
- short-circuit current
- Pd
- potential difference
- Gt
- tissue conductance
- W-7
- N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide hydrochloride
- W-5
- N-(6-aminohexyl)-1-naphthalenesulfonamide hydrochloride
- Received April 4, 2000.
- Accepted June 9, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|