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Available online on www.ijtpr.com International Journal of Toxicological and Pharmacological Research 2010; 2(3): 77-80 Influence of Lansoprazole on Anti-diabetic Effect of Pioglitazone in Normal Rats, Diabetic Rats and Normal Rabbits Suresh D. K1*, Loya P. J1, Kature D. V1, Gopala krishna C. H1, Khalid M. D1, Jyoti G. J1. 1 Department of Pharmacology, Luqman College of Pharmacy, Post Box No- 87,Old Jewargi road, Behind P & T colony, Gulbarga-585102, Karnataka, India. ABSTRACT The present study was carried out to evaluate the drug-drug interaction between anti-diabetic drug and anti-ulcer drug. Interaction of pioglitazone, thiazolidinedione anti-diabetic drug with lansoprazole (anti-ulcer drug) was evaluated in normal, streptozotocin induced diabetic rats and in normal rabbits. The blood samples were collected from normal, diabetic rats and in normal rabbits at different time interval upto 24hrs and blood glucose was estimated by GOD/POD method. Lansoprazole (30mg/kg p.o.) pretreatment has significantly enhance the peak hypoglycemic effect from 49.88 ± 2.90% to 58.75 ± 1.43% in normal rats and significantly enhanced the peak anti-diabetic effect from 52.40 ± 1.37% to 64.33 ± 1.69% in diabetic rats. Similarly pretreatment with lansoprazole (100mg/kg p.o.) has also significantly enhance the peak hypoglycemic effect from 35.89 ± 1.91% to 45.31 ± 0.56%. Duration of anti-diabetic effect was raised from more than 24hrs. this study indicates that therapeutic drug monitoring has to be required to re-adjust the therapeutic dose of lansoprazole and pioglitazone when they are used concomitantly. KEY WORDS: - Lansoprazole, pioglitazone, streptozotocin, anti-diabetic activity. INTRODUCTION that, the drug interaction may be fourth to sixth Drug interaction is the modification of the effect of leading cause for death in United States3, 4. one drug (object drug) by the prior or concomitant Diabetes mellitus – a metabolic disorder administration of another drug (precipitant drug). characterized elevated blood glucose levels requires Drug interaction may either enhance or diminish the lifelong treatment. Diabetic patients may also be intended effect of one or both drugs. It may modify affected with many other diseases like peptic ulcer, the diagnostic, preventive or therapeutic activity of hypertension and fungal infections, which require either drug1. In poly pharmacy, it is important to prolong treatment 5. determine the incidence of drug interactions, which There are reports that several patients suffering from serious implications, in hospitalized patients. In diabetes, are prone to peptic ulcer infections6. In such addition, it is also important to find out agents that are cases Antiulcer agent like omeprazole, pentaprazole, most likely to produce hazardous interactions2. As per lansoprazole, ranitidine etc and Thiazolidinedione survey, the incidence of drug-drug interaction ranges (Antidiabetic agents) like Pioglitazone is administered from 3 to 5% in patients taking a few drugs to 20% in patients receiving many drugs. According to a report There are reports that lansoprazole is known to inhibit Table no 1: Percentage decrease in blood glucose levels at different time intervals in normal rats. n=6, *significant at p<0.05; **highly significant at p<0.01; ***very highly significant at p<0.001. *Author for correspondence: [email protected] Suresh D. K, et al. Influence of Lansoprazole … cytochrome P-450 enzyme system7. Therefore the (10mg/kg p.o.) for rats, (25mg/kg p.o.) for rabbits present study was conducted on normal, diabetic rats respectively. Group-3 received lansoprazole (30mg/kg and normal rabbits to assess the influence of p.o.) for 7days on the 7th day, 6 hrs after lansoprazole pretreatment on the Antidiabetic effects administration of lansoprazole, the animals were fasted for 14hrs. on the 8th day, lansoprazole was given as usual. One hour after the treatment, animals of group-3 received Pioglitazone (10mg/kg p.o.). incase of rabbits group-3 received lansoprazole Study was conducted on normal, diabetic rats and (100mg/kg p.o.) for 7days. On the 7th day, 6hours normal rabbits (wistar strain) of either sex, weight after administration of lansoprazole, the animals were range 150-200g in rats, 1.5-1.8 kg in rabbits. The fasted for 14hours. On the 8th day, lansoprazole was animals were produced from Mahavir enterprises given as usual. One hour after the treatment, animals Hyderabad. They were housed under standard of group-3 received Pioglitazone (25mg/kg p.o.). conditions (temperature of 28 ± 2°C and 50 ± 2% blood samples were collected thereafter at above relative humidity with 12 hr light/dark cycle) and mentioned intervals and glucose levels were provided with water ad libitum. Prior approval by estimated. The percentage blood glucose reductions at institutional ethics committee (reg.no: various time intervals were calculated and compiled 146/1999/CPCSEA) was obtained for conduction of experiments. The study was conducted in the Statistical analysis: Department of Pharmacology of Luqman College of The data were analyzed by student ‘t” test. P values pharmacy, Gulbarga between 2009 and 2010. lower than 0.05 were considered as statistically Lansoprazole were obtained from Lee pharma Ltd Hyderabad. Pioglitazone obtained from Cadila RESULTS Pharma pvt.Ltd. Ahmedabad. Pioglitazone (10mg/kg It is evident from table no 1 and 2 that treatment with p.o.) and lansoprazole (30mg/kg p.o.) suspensions lansoprazole alone did not alter the blood glucose were prepared using 2% w/v gum acacia as levels in normal and diabetic rats. However, suspending agent. lansoprazole pretreatment (30mg/kg p.o.) has significantly enhance peak hypoglycemic effect from 49.88 ± 2.90% at 8th hr to 58.75 ± 1.43% at 8th hr. Diabetes was induced in the rats by administering Lansoprazole pretreatment (30mg/kg p.o.) has streptozotocin (50mg/kg) intraperitoneally into the significantly enhance peak anti-diabetic effect from 24hr fasted rats8,9. Blood samples were collected after 52.40 ± 1.37% at 8th hr to 64.33 ± 1.69% at 8th hr. and 24hrs and blood glucose levels were estimated. duration of hypoglycemic and anti-diabetic effect was Albino rats which have shown more than 200 mg/dl blood glucose levels were considered as diabetic. The Similarly pretreatment with lansoprazole (100mg/kg blood glucose levels were monitored for further 7 p.o.). has also significantly enhanced peak days. From this it was confirmed that diabetes was hypoglycemic effect from 35.89 ± 1.91% to 45.31 ± induced in 24 hrs and stabilized within 7days. These 0.56% at 12th hr duration of hypoglycemic effect was animals were used for further studies. The normal, diabetic rats and normal rabbits were marked conveniently and distributed randomly into three DISCUSSION groups of 6 animals each separately. All the animals Diabetes mellitus is a chronic metabolic disorder were over night fasted with water ad libitum. The requiring lifelong treatment. Peptic ulcer also requires animals in group-1 received lansoprazole (30mg/kg treatment for a prolonged period. If a patient is suffers p.o.) for rats, (100mg/kg p.o.) for rabbits respectively. from Diabetes mellitus as well as peptic ulcer, he has Animals in the group-2 received pioglitazone to use Antidiabetic drugs such as Thiazolidinedione Table no 2: Percentage decrease in blood glucose levels at different time intervals in diabetic rats. n=6, *significant at p<0.05; **highly significant at p<0.01; ***very highly significant at p<0.001. Suresh D. K, et al. Influence of Lansoprazole … like Pioglitazone and Antiulcer agent like lansoprazole pretreatment on the pharmacokinetic lansoprazole. In such instances, there is a possibility of occurrence of drug interactions. Our pilot study has Our studies in normal, diabetic rats and normal rabbits indicated that drug interactions occur when suggested that drug interaction occurs between lansoprazole and Pioglitazone are administered lansoprazole and Thiazolidinediones when they used concomitantly at therapeutic doses. However, the concomitantly in pathophysiological conditions like therapeutic dose was found to influence the Diabetes mellitus at very high dose. Antidiabetic effect significantly. In this present study, indicates clearly that during the For the assessment of the potentiation of Antidiabetic concomitant administration of thiazolidinediones and effect, onset of action, (time taken to reduce minimum lansoprazole at therapeutic doses, the dose and of 20% reduction in blood glucose levels), peak frequency of administration of Thiazolidinediones effect, duration of anti diabetic effect (duration in need to be readjusted. Simultaneously blood glucose which minimum of 20% reduction in blood glucose levels are monitored during treatment period as levels are maintained) were considered 5. precautionary measure so as to avoid severe Since lansoprazole (30mg/kg p.o.) perse did not hypoglycemia. influenced the blood glucose levels and thus the possibility of occurrence of pharmacokinetic CONCLUSION interaction can be ruled out. In our study, pretreatment The present study concluded that, during with lansoprazole (30mg/kg p.o.) altered the onset of simultaneous treatment of diabetes mellitus with action of Thiazolidinediones, where onset of action, peptic ulcer infections and therapeutic dose of peak effect and duration of Antidiabetic effect Thiazolidinediones and lansoprazole do interact. induced by Thiazolidinedione were significantly Therefore it is necessary to adopt therapeutic drug enhanced. This suggests that lansoprazole retards the monitoring so as to readjust dose and frequency of metabolism of these Antidiabetic drugs by inhibiting administration of these drugs, when they are used the enzymes responsible for their metabolism. There concomitantly to avoid the patients from severe are reports that Pioglitazone is mainly metabolized by CYP2C8, CYP2C9 and CYP3A45,10-11. Reports also indicate that lansoprazole is a weak inhibitor of ACKNOWLEDGEMENTS: CYP2C8 and CYP3A411-12. It is evident from the The authors are thankful to the principal Dr. Syed results that the therapeutic dose of lansoprazole Sanaullah for their encouragement and support enhanced the Antidiabetic effect of the Pioglitazone. This may be due to weak inhibitory effect of REFERENCES lansoprazole on CYP2C8 and CYP3A412. Further 1. Kohler GI et al. Elements of Clinical studies are undertaken to establish the influence of Table no 3: Percentage decrease in blood glucose levels at different time intervals in normal rabbits. n=6 *significant at p<0.05; **highly significant at p<0.01; ***very highly significant at p<0.001. Suresh D. K, et al. Influence of Lansoprazole … theophylline and antipyrine in man. Eur J Possible drug interactions in hospitalized 8. Kavalali G, Tuncel H, Goksel S, Hatemi HH. patients. The Ind J Hos Pharm 1998; 91-93. Hypoglycaemic activity of Urtica pilulifera in streptozotocin-diabetic rats. Journal of 9. Sevugan A, Subramanian K, Balamuthu K, activity of leaf and callus extracts of Aegle 4. Yuan R et al. In vitro studies; experience of 10. Prasad P Shitole, Sachin L Badole, Subhash Influence of Itraconazole on Antidiabetic Anti-hyperglycaemic activity of IND and its effect of Thiazolidinedione in Diabetic rats. interaction with glyburide and Pioglitazone 6. Lai KC, Lam SK, Chu KM. Lansoprazole for 11. Shannon F Manzi, Michael Shannon. Drud iteractions – a review. Clinical Pediatric aspirin use. N Eng J Med. 2002; 346:2033- 12. Rajendra SV, Raghuveer Gupta PS, Joshi 7. Roux A, Naline E, Molinier P, Dellatolas F, Influence of Lansoprazole on hypoglycaemic activity of oral Antidiabetic agents in healthy albino rats. Acta Pharmaceutical Turcica 2004; 46: 95-99.

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