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Pharmacokinetic interactions of glipizide with esomeprazole in normal, diabetic and ulcerative rats

International Journal of
Pharmaceutical Research &
Allied Sciences
Pharmacokinetic Interactions of Glipizide with Esomeprazole in
Normal, Diabetic and Ulcerative Rats
Research scholar, JJT University, Jhunjhune, Rajasthan, India1 Kalol institute of pharmacy, Kalol, Gujarat, India2 Abstract
The present study was carried out to evaluate the drug-drug interactions between esomeprazole and
glipizide. Interaction of esomeprazole (Eso), the known antiulcer drug with antidiabetic agent, glipizide
(Gli) was evaluated in healthy, diabetic and ulcerative rats. Single day (SD) and multiple day (MD)
pharmacokinetic studies were performed for glipizide and esomeprazole in normal, diabetic and ulcerative
animals. Blood samples were collected at 0, 0.25, 0.5, 1, 2, 4, 8 and 24 hours (hr) and pharmacokinetic
parameters were determined. Both single and multiple days treatment of glipizide has shown no effect on
pharmacokinetic profile of esomeprazole, while esomeprazole influenced the pharmacokinetic properties of
glipizide in both normal and diabetic rats. This may be due to inhibition of CYP (cytochrome P-450)
enzyme by esomeprazole, the enzyme through which glipizide gets metabolized. The findings of the
present study suggested that there is potential pharmacokinetic interaction between glipizide and
esomeprazole in rats.
Key words: Glipizide, Esomeprazole, Streptozotacin, Pharmacokinetic.
Introduction
In many chronic ailments, the multi drug therapy time, which may require chronic treatment such may be advocated to mitigate the severity of or as diabetes and gastric ulcer. As both diseases to avoid the development of possible resistance. require chronic treatment or chronically used as There is every possibility of occurrence of drug- prophylaxis. In any case, it can create a scenario drug interactions when multiple drugs were where one has to use multiple drug therapy for administered simultaneously. These interactions such diseases. This will lead to drug-drug may be so severe to cause mortality or may interactions, where one drug may influence the nullify the therapeutic efficacy of the treatment. pharmacokinetic or pharmacodynamic profile of Drug interactions have become a significant issue in health care system. These drug interactions can be explained by alteration in the Diabetes is a metabolic disorder of multiple pharmacokinetic parameters including inhibition alterations in pharmacodynamic properties of carbohydrate, fat and protein metabolism one or both of the drugs. Many of the major resulting from defects in insulin secretion, pharmacokinetic interactions occur due to insulin action, or both. There are reports that induction or inhibition of hepatic cytochrome several patients suffering from diabetes are prone P450 enzymes1,2. There are certain patients who to peptic ulcer infections4. Antiulcer drugs such may be suffering with more than one disease at a as ranitidine, famotidine, omeprazole and lansoprazole potentiates the action of many a dose of 1 mg/kg per day for a period of 12 weeks. At the end of 12 weeks, animals were concomitantly for a prolong period of time5,6,7. Glipizide is an oral hypoglycemic agent, which is a commonly prescribed drug for the treatment Pharmacokinetic interaction study in normal,
of patients with type II diabetes mellitus8 and it diabetic and ulcerative rats:
is extensively metabolized in the liver by CYP2C99 and CYP3A410,11,12. Esomeprazole is a Wistar rats were randomly distributed into different groups of six animals in each group. polypropylene cages and maintained on uniform diet and temperature with 12 hr light and dark cycle. Glipizide was administered at a dose of 50 On perusal of literature survey, we found that the mcg/kg and esomeprazole at a dose of 30 mg/kg, interaction of glipizide and esomeprazole has not orally to their respective groups. These animals been elucidated. Therefore, the present study was were mainly divided into two sub groups as conducted to assess the interaction between follows: Normal and diseased animals. In normal esomeprazole and glipizide in normal, diabetic rats, Group 1 was vehicle control, which received vehicle. Group 2 and 3 were served as treatment groups, which received esomeprazole and glipizide respectively. Group 4 was served as treatment group (SD), which received Materials and Methods
esomeprazole, followed by glipizide after 30 minutes. Group 5 was served as treatment group Drugs: Esomeprazole was purchased from
(SD), which received glipizide, followed by Sigma–Aldrich Co, St Louis, MO, USA and esomeprazole after 30 minutes. Group 6 was glipizide was obtained as gift samples from served as treatment group (MD), which received Matrix Pvt. Ltd, Hyderabad. All other chemicals esomeprazole for 8 days, followed by glipizide after 30 minutes on 8th day. Group 7 was served as treatment group (MD), which received Experimental animals: Wistar rats weighing
glipizide for 8 days, followed by esomeprazole 200 to 250 g were used for the present study. Animals were housed under a standard 12 hr: 12hr light/dark cycle and were provided with In disease rats, Group 1 and 2 were served as food and water ad libitium. Animals were diabetic and ulcerative control, which received acclimated to laboratory conditions before vehicle. Group 3 rats were diabetic which testing. The animal protocol was approved by the received glipizide and group 4 rats were Institutional Animal Ethical Committee of Kalol ulcerative which received esomeprazole. Group 5 rats were diabetic (SD), which received esomeprazole, followed by glipizide after 30 Experimental procedures:
minutes. Group 6 rats were ulcerative (SD), Streptozotacin (STZ) induced diabetes14: At
esomeprazole after 30 minutes. Group 7 rats neonatal stage, STZ was administered at day 2 and day 3 of birth at a dose of 45 mg/kg in citrate esomeprazole for 8 days, followed by glipizide buffer at pH 4.5, which result in diabetic after 30 minutes on 8th day. Group 8 rats were condition. At the end of 8th week of their age, ulcerative (MD), which received glipizide for 8 oral glucose tolerance test was done at a dose of days, followed by esomeprazole after 30 minutes 3 g/kg of glucose to evaluate the diabetic condition in rats. The rats which have 45% high glucose AUC compared to normal control were All the animals were over night (12 hours) fasted administered with their respective treatments. Indomethacin induced chronic gastric ulcer15:
Blood was collected at 0, 0.25, 0.5, 1, 2, 4, 8 and The rats were treated with indomethacin orally at 24th hour. Samples were centrifuged at 8000 rpm for 10 minutes, plasma was collected and potentiate the pharmacokinetic profile of glipizide in both normal, (AUC, 77.44±4.13 vs. 58.12±2.51, P<0.05), (Cmax, 8.54±0.27 vs. Pharmacokinetic
analysis16:
maximum plasma concentration (Cmax), time 83.77±5.82 vs. 65.00±4.77, P<0.05), (Cmax, concentration– time curve (AUC0–24), mean 4.11±0.09 vs. 3.37±0.13, P<0.001) rats. While residence time (MRT), elimination rate constant (Kel) and half life (T1/2) were calculated using improvement in pharmacokinetic properties of non compartmental pharmacokinetic model of In multiple days treatment, esomeprazole shown Statistical analysis: All the means are presented
significant increase in the pharmacokinetic with their standard error mean (mean ±SEM). parameters of glipizide in both normal (AUC, The pharmacokinetic parameters were compared 106.42±6.15 vs. 58.12±2.51, P<0.001), (Cmax, using one-way ANOVA, followed by Dunnett 11.92±0.22 vs. 6.73±0.45, P<0.001), (T1/2, 4.71±0.10 vs. 3.23±0.24, P<0.001) and diabetic (AUC, 104.91±6.73 vs. 65.00±4.77, P<0.01), (Cmax, 12.05±0.30 vs. 7.35±0.33, P<0.001), (T1/2, 4.98±0.06 vs. 3.37±0.13, P<0.001) rats. While The mean plasma levels were evaluated for glipizide and esomeprazole alone and their improvement in pharmacokinetic properties of combinations in both normal and diseased condition. In single dose study, Glipizide alone has shown significant increase in Cmax in both normal and diabetic condition (table-1 and 2). Table 1: Mean pharmacokinetic parameters of glipizide alone and during esomeprazole treatment in
normal rats

Glipizide+Esomeprazole Glipizide+Esomeprazole
Parameters
Glipizide
Mean ±SEM (n=6), ***p<0.001, **p<0.01, *p<0.05 compared to glipizide control.

Table 2: Mean pharmacokinetic parameters of glipizide alone and during esomeprazole treatment in
diabetic rats

Glipizide+Esomeprazole Glipizide+Esomeprazole
Parameters
Glipizide
Mean ±SEM (n=6), ***p<0.001, **p<0.01, *p<0.05 compared to glipizide control.
Table 3: Mean pharmacokinetic parameters of esomeprazole alone and during glipizide treatment in
normal rats

Esomeprazole+Glipizide Esomeprazole+Glipizide
Parameters
Esomeprazole
Mean ±SEM (n=6), ***p<0.001, **p<0.01, *p<0.05 compared to esomeprazole control.
Table 4: Mean pharmacokinetic parameters of esomeprazole alone and during glipizide treatment in
ulcerative rats

Esomeprazole+Glipizide Esomeprazole+Glipizide
Parameters
Esomeprazole
Mean ±SEM (n=6), ***p<0.001, **p<0.01, *p<0.05 compared to esomeprazole control.
Fig.1. Plasma concentrations time curves of (Gli) glipizide following its oral administration at 50
mcg/kg in control and (Eso) esomeprazole (30 mg/kg) pre-treated (SD & MD) normal (A) and
diabetic (B) rats. Data are expressed as mean±SEM in (n = 6) rats.
Fig.2. A, B, C and D, E, F represent pharmacokinetic parameters in normal and diabetic rats
respectively. Half life, Cmax and AUC of glipizide following its oral administration at 50 mcg/kg in
control and esomeprazole (30 mg/kg) pre-treated (SD & MD) normal (A,B,C) and diabetic (D,E,F)
rats respectively. Data are expressed as mean±SEM in (n = 6) rats.
Discussion
assessed by interaction between these drugs in Chronic elevation of blood glucose levels leads both normal and diseased rats. Single dose study to many co-existing complications like diabetic showed that glipizide administration did not retinopathy, diabetic neuropathy, delay in potentiate the pharmacokinetic parameters of healing of gastric ulcer, diabetic foot ulcer. Drug esomeprazole. Glipizide has not shown any therapy in Type II diabetes becomes more complex as many individuals are on multiple metabolism and excretion of esomeprazole in drug therapy and administer many drugs during both healthy and diseased rats, which indicates the same period of time to treat secondary no significant interaction occurred. While, single diabetic complications17. A closer monitoring dose administration of esomeprazole stimulated and supervision of drug therapy is required so the pharmacokinetic profile of glipizide in both that drug related problems can be prevented or healthy and diabetic rats which indicates an detected at an early stage. An increasing number inhibition of glipizide metabolism leading to of drug related problems are caused by drug interactions17. Currently, the management of glipizide in both normal and diabetic rats. This type II diabetes becoming more complex since confirmed interaction occurred at absorption site. Prior administration of esomeprazole further combination drug therapy has increased the risk increases the half life and decreases the Kel when of pharmacokinetic interactions in patients with compared with glipizide alone which indicates diabetes18. The activity of one drug could alter interaction occurred at metabolism and excretion the pharmacokinetics of another drug and it may site also. In multiple dose study, repeated dosing be due to risk of the enzyme inverse reaction pharmacokinetic profile of esomeprazole in both healthy and ulcerative rats. Hence, interaction at absorption, metabolism and excretion site has Esomeprazole, the (S)-isomer of omeprazole, is been ruled out. While, seven days administration the first proton pump inhibitor developed as a of esomeprazole increased the Cmax and also single isomer for the treatment of acid-peptic shown significant increase in AUC of glipizide which indicate potential absorption profile of glipizide in both normal and diabetic condition. isoenzyme in the liver13. Glipizide is highly On metabolism and excretion, esomeprazole has potent second generation sulfonylurea derivative shown significant increase in half life and which is used for the treatment of type II decreases the Kel when compared with glipizide diabetes mellitus. Glipizide is extensively alone which indicates interaction occurred at metabolism and excretion site also. These data CYP3A410,11,12. Alteration in pharmacokinetic confirmed that concomitant administration of profile of esomeprazole and glipizide was glipizide and esomeprazole might result in pharmacokinetic interaction. The above results delivery systems of glipizide, Eur. J. pharm. 9. Kidd, R.S., Straugh, A.B., Meyer, M.C., esomeprazole increased the plasma levels of Blaisdell, J., Goldstein, J.A., Dalton, J.T., glipizide in both normal and diabetic rats. The mechanism involved in this interaction may be phenytoin, glipizide and nifedipine in an the inhibition of CYP3A4 enzyme, the enzyme responsible for metabolizing glipizide by allele, Pharmacogenetics, 1999, 9, 71-80 10. Peart, G.F., Boutagy, J., Shenfield, G.M., The “Cite this article”
known debrisoquin phenotype, Clin. Pharm. J. Singh, S.Patel “Pharmacokinetic Interactions of Glipizide with Esomeprazole in Normal, Diabetic and Ulcerative Rats.l Int. J. of Pharm.
hypoglycemic drug, Am. J. Med. Sci., 1989, Res. & All. Sci.2013; Volume 2, Issue 1,49-55 12. Brian W.R., Metabolic drug interactions. Philadelphia: Lippincott Williams & Wilkins; References:
13. Andersson, T., Hassan-Alin, M., Hasselgren, 1. Tanaka, E., Clinically important drug G., Rohss, K., Drug interaction studies with interactions: role of CYP enzymes, J. Clin. esomeprazole, the (S)-isomer of omeprazole, 14. Pascoe, W.S., Jenkins, A.B., Kusunoki, M., determinants of glycaemia in a rat model of polymorphic hydroxylations of debrisoquine and S-mephenytoin, Clin. Pharmacol. Ther., mellitus, Diabetologia, 1992, 35(3), 208-15 15. Xiang, Z., Jian-Min, Si., Huai-De, H., 3. Alan S., Nies., Stephen., Spielberg P. inducing factors, World J. Gastroenterol., 16. Prashanth, S., Kumar, A.A., Madhu, B., Rama, N., VidyaSagar, J., Pharmacokinetic and pharmacodynamic drug interactions of carbamazepine and glibenclamide in healthy recurrences of ulcer complications form long- term low-dose aspirin use, N. Eng. J. Med., Visweswaram, D., Influence of ranitidine on Bioavailability studies of Pioglitazone with the hypoglycemic activity of tolbutamide and Antacid –An Invivo Evaluation in Human glibenclamide in rabbits, Ind. J. Physiol. Preclinical and Pharmaceutical Research, 6. Rajendra, S.V., Influence of lansoprazole on 18. Sudhir, N., Umathe., Pankaj, V.D., Quercetin antidiabetic agents in healthy albino rats, pretreatment increases the bioavailability of Acta Pharmaceutica Turcica, 2004, 46, 95-99 pioglitazone in rats: Involvement of CYP3A4 7. Kumar, V., Venakat, R.N., Ramachandra, S., inhibition, Biochemical Pharmacology, 2008, Influence of omeprazole on hypoglycaemic activity of glibenclamide and tolbutamide in 19. Michael, A., Wynalda, J., Hutzler, M., Invitro normal albino rabbits, Acta Pharmaceutica and intestinal microcosms, Drug metabolism 8. Verma, R.K., Garg, S., Development and evaluation of osmotically sustained oral drug

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