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Journal of Advanced Pharmaceutical Sciences
Prasad Neerati et. al
2011 Vol-1 Issue 1
INFLUENCE OF ITRACONAZOLE A P-GLYCOPROTEIN PRASAD NEERATI, * MURALIKRISHNA GADE.
DMPK & Clinical Pharmacology Division Department of Pharmacology, University College of Pharmaceutical Sciences, Kakatiya University, Warangal, India-506 009. The present study was aimed at investigating the effect of Itraconazole, a p-glycoprotein inhibitor on the pharmacodynamics of glibenclamide in normal and diabetic rats. Experimental diabetes in rats was induced by injecting alloxan monohydrate (i.p) at a dose of 120 mg/kg in ice cold normal saline. The normal and diabetic rats were randomly divided into different groups and glibenclamide (5mg/kg, p.o) was administered to normal saline or itraconazole pretreated (30mg/kg, p.o, for 7 days) groups. The blood samples were collected for a period of 24h in normal and diabetic rats and the serum samples were analyzed for glucose levels. The percentage reduction in blood glucose levels were calculated with respect to initial levels. Glibenclamide showed a significant reduction of elevated and normal blood glucose levels. The extent of blood glucose reduction with glibenclamide was comparatively increased in itraconazole pretreated group. The present study results suggest that, itraconazole enhanced the hypoglycemic activity of glibenclamide by affecting the disposition of glibenclamide, possibly .Key words: Itraconazole, glibenclamide, hyperglycemia, p-glycoprotein
Journal of Advanced Pharmaceutical Sciences
Prasad Neerati et. al
2011 Vol-1 Issue 1
INTRODUCTION
Diabetes mellitus is the most common endocrine disorder characterized by hyperglycemia, altered metabolism of lipids, carbohydrates, and proteins, and an increased risk of complications from vascular disease. [1], [2] The management of diabetes mellitus involves utilization of various drugs to save the life and alleviate symptoms; secondary aims are to prevent long-term diabetic complications and by eliminating various risk factors to increase longevity. During such a therapy, there is every possibility of occurrence of drug interactions, which may produce serious and deleterious effects to the patients. Most of the drugs used in the current therapy have the capacity to influence many physiological systems.[3] Two drugs concomitantly administered will often affect some of the same systems. Oral hypoglycemic agents like sulfonylureas, biguanides, alphaglucosidase inhibitors, meglitinide analogs, and thiazolidinediones are useful in the treatment of type 2 diabetes mellitus.[1] (Bastaki, 2005). Fungal infections are the most common co-morbid condition present along with diabetes and involves various drug therapies in which anti fungal agents like triazole derivatives are common.[4] Azole derivatives fluconazole, miconazole, ketacoazole are reported that they increase the blood glucose reducing effect of sulfonylureas by cyp2c9 inhibition.[4],[5] In the present study we used glibenclamide as a objective drug because it act as substrate for p-glycoprotein and our antifungal agent itraconazole act as p-glycoprotein inhibitor. [6],[5],[7] Based on the above evidence, this study was designed to elaborate on the pharmacodynamic interactions that may exist between Journal of Advanced Pharmaceutical Sciences
Prasad Neerati et. al
2011 Vol-1 Issue 1
MATERIALS AND METHODS
Glibenclamide (Aurobindo, Hyderabad, India) and itraconazole (Sun Pharmaceuticals Ltd, Mumbai, India) were obtained as a gift samples. The glucose estimation kits were obtained from Excel diagnostics Pvt. Ltd, Hyderabad, India. Study design
The protocol of the study was approved by Institutional Animal Ethics Committee (IAEC) of University College of Pharmaceutical Sciences, Kakatiya University, Warangal. Adult Wistar rats of either sex, weighing 200-250 g, were selected and maintained at a constant temperature of 26 ± 2oC and humidity 30-40% with 12 h light/dark cycle. The animals were allowed to acclimatize to the environment for 7 days and supplied with a standard pellet diet and water ad libitum. Experimental induction of diabetes
Experimental diabetes in rats was induced by injecting alloxan monohydrate (i.p) at a dose of 120 mg/kg in ice cold normal saline. After 72 h, samples were collected from rats by orbital puncture of all surviving rats and the serum was analyzed for glucose levels[4], [8] Rats with blood glucose levels of 200 mg/dl and above were considered as diabetic and selected Pharmacodynamic interaction in diabetic rats
The diabetic rats were randomly divided into three groups of eight animals each. All the animals were subjected to fasting for 18 h prior to experimentation and during the course of time; the animals had free access to water. Group I (C): served as control, received normal saline.
Group II (G): received glibenclamide at a dose of 5mg/kg (p.o) and
Journal of Advanced Pharmaceutical Sciences
Prasad Neerati et. al
2011 Vol-1 Issue 1
Group III (I +G): These rats were pretreated with itraconazole (30mg/kg, p.o) for 7 days and
on 8th day; glibenclamide (5mg/kg, p.o) was administered after 1 hr of itraconazole Collection of blood samples
The blood samples were collected before and after administration of the drugs at 0,2, 4, 8, 12, and 24 h by retro-orbital puncture method. The samples were centrifuged, and the separated serum was subjected to glucose estimation by glucose peroxidase method.[4] The percent reduction of blood glucose levels at each time was calculated with respect to Pharmacodynamic interaction in normal rats
In this study healthy normal rats (200-250 gm) were taken and divided in to three groups of eight in each. Group I (C) served as control, received normal saline. Group II (G)
received glibenclamide (5mg/kg, p.o) and Group III (I+G) these rats were pretreated with
itraconazole (30mg/kg, p.o) for 7 days and on 8th day, glibenclamide 5mg/kg was administered after 1 hr of itraconazole administration. The blood samples were collected at predetermined intervals and the serum samples were analyzed for glucose levels. Statistical significance
The data represented as mean ± SD. The significance of the observed difference in the pharmacodynamic parameters of glibenclamide and in combination with itraconazole was assessed by student’s unpaired t-test. A value of p<0.05 was consider to be statistically The initial blood glucose levels (92.8 ± 6.10 mg/dl) were increased with administration of alloxan to 396.4 ± 55.17 mg/dl indicates the successful induction of Journal of Advanced Pharmaceutical Sciences
Prasad Neerati et. al
2011 Vol-1 Issue 1
The percentage reduction of blood glucose levels in normal and diabetic rats with glibenclamide (5mg/kg) is shown in figure 1. In diabetic rats, glibenclamide showed a maximum reduction of 64.8% at 8th hour of drug administration. In normal rats, the maximum reduction of 50% was observed at second hour. The % reduction of blood glucose levels in normal and diabetic rats, exhibited by glibenclamide after treatment with itraconazole is shown in figure2.
Multiple dose interaction study revealed that the maximum % reduction in blood glucose levels, exhibited by glibenclamide after treatment with itraconazole was increased in normal rats was 8% at 2nd hour (p<0.05) and in diabetic rats, it was 9%, 13.2%, 17.7, 9.9, 9.4 at 2, 4, 8, 12 and 24 hours respectively (p<0.05). Figure 1 : The percentage reduction(mg/dl) in blood glucose levels of normal rats
with glibenclamide before and after treatment with Itraconazole.
Interaction in Normal rats
Be fore pre -
tre atm e nt
Afte r pre -
tre atm e nt
X axis=Time (Hours) and Y axis = percentage glucose reduction(mg/dl). Journal of Advanced Pharmaceutical Sciences
Prasad Neerati et. al
2011 Vol-1 Issue 1
Figure 2: The percentage reduction in blood glucose levels of diabetic rats with
glibenclamide before and after treatment with itraconazole.
Interaction in Diabetic rats
Before pre-
treatm ent
After pre-
treatm ent
DISCUSSION
Drug interactions are usually seen in clinical practice and the mechanisms of interactions are evaluated usually in animal models. We studied the influence of itraconazole on the pharmcodynamics of glibenclamide in normal and diabetic rats. The normal rat model served to quickly identify the interaction and diabetic rat model served to validate the same response in the actually used condition of the drug. The impact of drug transporters on pharmacokinetics has been widely recognized in the past few years. Several transporters with different functions have been characterized in various organs. P-glycoprotein, a product of the multi drug resistance gene, is one of the most studied drug transporters and belongs to the super family of ABC protein . Like the CYP enzymes, p-glycoprotein is also able to interact with a large number of structurally distinct drugs and genobiotics. [9] The known substrates for p-glycoprotein include a number of anti cancer agents and other drugs, such as digoxin [9] of the anti diabetic drug studied, glibenclamide is a substrate for the p-glucoprotein,[10] and verapamil, an inhibitor of p- Journal of Advanced Pharmaceutical Sciences
Prasad Neerati et. al
2011 Vol-1 Issue 1
Glibenclamide is a second generation sulfonylurea, useful in the treatment of type 2 diabetic patients. These sulfonylurea agents are metabolized by CYP 2C9, 3A4 enzymes and glibenclamide is a substrate of p-glycoprotein (p-gp) efflux transporter. The pharmacodynamics of glibenclamide is influenced by p-gp inhibitors like itraconazole. The present study showed a significant statistical difference in % reduction of blood glucose levels between the normal and diabetic rats (p<0.05). As well as in multiple dose study revealed an increased % reduction of blood glucose levels in diabetic and normal rats is due to the inhibition of p-gp by itraconazole. Evidencing a possible pharmacodynemic interaction between glibenclamide with itraconazole.There is a statistically significant difference in glucose levels was observed between the single dose and multiple dose studies in diabetic rats (P<0.05). But in case of normal rats, statistical difference in glucose levels was observed at CONCLUSION
In conclusion that, itraconazole enhanced the hypoglycemic activity of glibenclamide by affecting the disposition of glibenclamide, possibly by the inhibition of p-glycoprotein and heighiliting the necessity to readjust the dose of glibenclamide when co-administered with Acknowledgements
The authors wish to thank to AICTE, New Delhi, India, for providing financial assistance. Journal of Advanced Pharmaceutical Sciences
Prasad Neerati et. al
2011 Vol-1 Issue 1
REFERENCE:
1. S Bastaki (2005). Diabetes mellitus and its treatment. Int J Diabetes Metab.; 13: 2. M Svensson, JW Eriksson, G Dahlquist (2004). Early glycemic control, age at onset, and development of microvascular complications in childhoodonset type 1 diabetes: A population-based study in northern Sweden. Diabetes Care,27:955-62. 3. V Mohan (2005). Handbook of diabetes mellitus, Chennai. 99. 4. E Bailey., D Karkovsky, and M Rybak (1990). The triazole antifungal agents: a
review of itraconazole and fluconazole. Pharmacotherapy., 10:146– 153
5. JA Endicott, V Ling (1989). The biochemistry of P-glycoproteinmediated multidrug resistance. Annu. Rev. Biochem., 58:137–171. 6. J Heykants, M Michiels, W Meuldermans, J Monbaliu, K Lavrijsen, A Peer, JC Levron, R Woestenborghs, G Gauwenbergh (1987). The pharmacokinetics of itraconazole in animals and man: an overview, 223– 249. 7. McClean, GJ Sheehan (1994). Interaction between itraconazole and digoxin. Clin. 8. P Trinder (1969). Determination of glucose in blood using glucose oxidase with an alternative glucose acceptor. Ann Clin Bioche., 6:24-7. 9. PE Goldstein, A Boom, J Van Geffel, P Jacobs, B Masereel, R Beauwens (1999). P- glycoprotein inhibition by glibenclamide and related compounds. Pflugers Journal of Advanced Pharmaceutical Sciences
Prasad Neerati et. al
2011 Vol-1 Issue 1
10. CG Semple, C Omile, KD Buchanan, GH Beastall, KR Paterson (1986). Effect of oral verapamil on glibenclamide stimulated insulin secretion. Br J Clin Pharmacol Assistant Professor Department of Pharmacology, University College of Pharmaceutical Sciences, Kakatiya University, Warangal – 506 009, A.P, INDIA Tel : +91-870-2461433. Fax : +91-870-2438844. E-Mail:

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