 |
| About Bioline | All Journals | Testimonials | Membership | News |
|
||||||
|
||||||
Indian Journal of Pharmacology, Vol. 38, No. 5, September-October, 2006, pp. 357-358 Research Letter The effect of rabeprazole and its isomers on aspirin and histamine-induced ulcers in rats Bodhankar SL, Jain BB, Ahire BP, Daude RB, Shitole PP Department of Pharmacology, Poona College of Pharmacy, Bharati Vidyapeeth Deemed University, Erandwane, Pune-411038, Maharashtra Code Number: ph06099 All currently available proton pump inhibitors (PPI) are substituted benzimidazole pro-drugs and chiral compounds. Rabeprazole is an inhibitor of the gastric proton pump. It causes dose-dependent inhibition of acid secretion and has a more rapid onset of action than omeprazole.[1] Rabeprazole is mainly reduced via the non-enzymatic pathway to rabeprazole-thioether. Therefore, the acid inhibitory effects of rabeprazole are less influenced by CYP2C19 genotype status[2] and therefore, may be preferred in a population with a high incidence of CYP2C19 poor metaboliser status. Among the PPIs, omeprazole, lansoprazole, pantoprazole and rabeprazole are marketed as racemic mixtures of R- and S-enantiomers.[3] S-enantiomers of omeprazole and pantoprazole are also marketed separately. Rabeprazole is available as a racemic mixture of two isomers - R (+)- isomer (Dexrabeprazole) and S (-)- isomer in 1:1 proportion.[4] The objective of the present study was to investigate the anti-ulcer activity of R (+)- and S(-)-rabeprazole in aspirin- and histamine-induced ulcers in rats. Samples of racemate, R- and S-isomers of rabeprazole, aspirin and histamine were supplied by Emcure Pharmaceuticals Ltd., Pune, India. The doses of racemate, R- and S-isomers of rabeprazole were 1.25, 2.5, 5 and 10 mg/kg body weight, respectively. Rabeprazole and its isomers were dissolved in normal saline (0.9%). Aspirin (900 mg/kg, p.o.) and histamine (7.5 mg/kg, i.p.) were used for ulcer induction.[7], [8] Aspirin was suspended in sodium carboxy methyl cellulose (0.5% w/v) and histamine was dissolved in distilled water. Control animals were injected with normal saline. Wistar albino rats of either sex (180±10 g) were purchased from the National Toxicology Centre, Pune and Yash Farms, Pune. The animals were housed in polypropylene cages at 25± 1°C and relative humidity of 45-55% in a clean environment under 12:12 light:dark cycle. The animals had free access to food pellets (Chakan Oil Mill, Pune, India) and were provided filtered water ad libitum , during housing. The experimental protocol was approved by the Institutional Animal Ethics Committee (IAEC) of the Poona College of Pharmacy. In the aspirin-induced ulcer model, the animals were deprived of food for 36 hours before the experiment. Each group, consisting of 6 animals of either sex, having mean body weight of 180±10 g received aspirin (900 mg/kg, body weight orally), 60 min after the intraperitoneal administration of the test drug or vehicle (control). The rats were sacrificed 6 h later and their stomachs were excised and fixed with 1% formalin. Every opened and spread-out stomach was photographed at X7 magnification and the ulcer area was measured by superimposing graph paper with minimum square equal to 1 mm 2. In the histamine-induced ulcer model, the selection of the animals and the housing conditions were the same as described above. The animals were grouped as 6 rats per group, with a total of 5 groups, and marked for identification before the commencement of the experiment. The animals were deprived of food for 24 hours before the commencement of the experiment. Each group received histamine (7.5 mg/kg, body weight, i.p.), 30 min after the intraperitoneal administration of the test drug or vehicle (control). The rats were sacrificed 4 h later, Their stomachs were excised and fixed with 1% formalin. Every opened and spread-out stomach was analysed as described above. The results are expressed as mean±SD and presented in [Table - 1]. A comparison between the groups was made using the one-way analysis of variance (ANOVA), followed by Dunnett's test. Aspirin (900 mg/kg) produced punctate lesions on the glandular portion of the rat stomach with mean±SD area of 5.07±1.70 mm 2. Both isomers of rabeprazole dose- dependently reduced the number of ulcers and mean ulcer areas as shown in [Table - 1]. R(+)-rabeprazole (10 mg/kg) was more effective than S(-)-rabeprazole (10 mg/kg) and racemate rabeprazole (10 mg/kg). Histamine (7.5 mg/kg) produced ulcers in rats with mean±SD area of 10.31±2.52 mm 2. Histamine-induced ulcers were inhibited dose-dependently by racemate rabeprazole and isomers as shown in [Table - 1]. R (+)-rabeprazole (10 mg/kg) was more effective than S (-)-rabeprazole (10 mg/kg) and equally effective as racemate rabeprazole (10 mg/kg). The analysis of data shows that using equal doses, in the aspirin-induced ulcer model, the ratio (R-isomer % inhibition ulcer area):(racemate % inhibition ulcer area) is 1.93± 0.9 , while in the histamine-induced ulcer model, the ratio is 1.1± 0.09. This shows that in its cytoprotective action, the R-isomer showed almost twice the ulcer protective effect as produced by racemate, at equivalent doses. Using half-dose of R-isomer compared to racemate, in the aspirin-induced ulcer model, the ratio (R-isomer % inhibition ulcer area):( racemate % inhibition ulcer area) is 1.34± 0.19, while, in the histamine-induced ulcer model, the ratio is 0.94± 0.04. Hence, approximately 50% of the dose of R-isomer is adequate to obtain equal antiulcer response with the racemate. The corresponding values for the S-isomer are as follows. Using equal doses, in the aspirin-induced ulcer model, the ratio (S-isomer % inhibition ulcer area):(racemate % inhibition ulcer area) is 1.04± 0.2, while, in the histamine-induced ulcer model, the ratio is 0.43± 0.5. Using half-dose of S-isomer compared to racemate, in the aspirin-induced ulcer model, the ratio (S-isomer % inhibition ulcer area):(racemate % inhibition ulcer area) is 0.70± 0.06 (mean± SD), while, in the histamine-induced ulcer model, the ratio is 0.26± 0.38. Ratios of less than 0.9 indicate that the S-isomer is less effective than the R-isomer. The critical factors in maintaining the defense and integrity of the gastric and intestinal wall, mediated by prostaglandins, are mucosal blood flow, mucus and bicarbonate secretion, epithelial proliferation and repair.[5] Aspirin induces gastric lesions through blocking prostaglandin production.[6] Rabeprazole was reported to significantly increase the production of mucin (a defense factor) in rats. It prevented or reduced the size of gastric ulcers caused by water immersion in rats. It also prevented stress-induced increase in gastric mucosal peptide-leukotrine content with differing mucosal prostaglandin levels.[7] In the present study, rabeprazole caused dose-dependent inhibition of aspirin-induced ulceration. R(+)-rabeprazole appears to be the major isomer having anti-ulcer activity. The induction of experimental gastric ulcers by histamine administration has long been recognised and is mediated through enhanced gastric acid secretion and vasospastic action of histamine. The model of histamine-induced ulcer in Guinea pigs has been described earlier.[8] In the present study, rats were used. Histamine-induced gastric ulcers were inhibited by racemate rabeprazole and its isomers. R-rabeprazole was found to be more effective than the racemate and S-rabeprazole. In the present study, we provide the evidence that R (+)-rabeprazole (Dexrabeprazole) is more effective than S (-)-rabeprazole and the racemate in inhibiting acid related gastric lesions in rats. Acknowledgments The author would like to thank Dr. S.S. Kadam, Principal and Dr. K.R. Mahadik, Vice-Principal, BVDU'S Poona College of Pharmacy for their keen interest and Emcure Pharmaceuticals, Pune for financial support.References
Copyright 2006 - Indian Journal of Pharmacology The following images related to this document are available:Photo images[ph06099t1.jpg] |
| |||||||||
