Clinical Pharmacy

A Study on Drug-Drug Interaction of Esomeprazole and Anti-Diabetic Drugs
Swamy VKM, Setty RS1, Shankaraiah MM, Jyothi TM, Rajendra SV
Department of Pharmacology, S.C.S. College of Pharmacy, Harapanahalli - 583 131, Karnataka, India, 1 College of Clinical Pharmacy, King Faisal University, Alahsa - 31982, Kingdom of Saudi Arabia Address for correspondence: Dr Ramachandra Siddam Setty; E-mail: rssiddamsetty@rediffmail.com

ABSTRACT Drug–drug interaction between esomeprazole at therapeutic and higher doses and sulfonylureas was studied. Sulfonylureas (tolbutamide 40 mg/kg and glibenclamide 40 μg/kg) were administered and the time to onset of hypoglycemia, the duration of the hypoglycemia, and the peak hypoglycemia were determined. Esomeprazole (1.8 mg/kg, 3.6 mg/kg, and 30 mg/kg) was administered for 8 days and its influence on sulfonylurea-induced hypoglycemia was studied. Therapeutic doses of esomeprazole, i.e., 1.8 mg/kg and 3.6 mg/kg dose did not influence the hypoglycemia induced by sulfonylureas. However, a higher dose, i.e., 30 mg/kg, did significantly enhance the duration of hypoglycemia and the peak hypolgycemia. Esomeprazole (30 mg/kg) by itself did not reduce the blood glucose levels; therefore, a pharmacodynamic type of drug interaction can be ruled out. Similarly, a pharmacokinetic type of drug interaction may be ruled out at therapeutic doses. The CYP isoenzyme system involved in the metabolism of sulfonylureas are not very sensitive to esomeprazole and the dose and frequency of administration of sulfonylurea need not be readjusted when they are used concomitantly with esomeprazole (at therapeutic doses). Key words: Drug–drug interaction, esomeprazole, glibenclamide, tolbutamide
DOI: 10.4103/0975-1483.71624

INTRODUCTION

Drug–drug interactions may occur when more than one drug is administered in a patient to treat a single ailment or multiple ailments. These concomitantly used drugs may either cause pharmacodynamic or pharmacokinetic types of interactions. The net result of both the types of interactions is the alteration in the therapeutic effect of either or both the drugs. There are several diseases that require treatment for the lifetime, e.g., diabetes and hypertension. Patients with such diseases will often need to be administered drugs for treatment of other co-existing diseases, either for a short period or lifelong. There is then a possibility of occurrence of interactions between drugs, resulting in either reduced or enhanced effects of any of
424

the drugs. Therefore, monitoring and readjustment of the dose/s is often necessary to optimize treatment. In the present study, two diseases (diabetes and gastric ulcers) that may co-exist and require chronic treatment were considered and the occurrence of interaction between the concurrently used drugs was assessed Diabetes mellitus is a disease characterized by elevated blood glucose levels. It requires treatment for prolonged periods, usually lifelong. Diabetic patients may also have other diseases, e.g., peptic ulcers, infectious diseases, etc. In such situations, treatment for the different ailments will have to be given simultaneously. Peptic ulcer is one such disorder that requires treatment for a prolonged period. There are several patients who suffer from both
Journal of Young Pharmacists Vol 2 / No 4

2. pretreatment with lansoprazole has been shown to enhance the peak hypoglycemia and the duration of hypoglycemia induced by glibenclamide in healthy rabbits. In such patients. 5. On the 8th day. and the duration of hypoglycemia (i. Hence.[7] However. 30. 6. maintained under standard conditions. and groups 3 and 6 received esomeprazole 30 mg/kg for a period of 8 days. after fasting for 18 hours all the animals of groups 1. There are reports that H2-receptor blockers such as ranitidine inhibit the metabolism of sulfonylureas and enhance their bioavailability.2] Similarly. the duration for which at least 20% reduction in blood glucose level maintained) was 40 h. there is a report that omeprazole increased the duration of hypoglycemia and peak hypoglycemia induced by sulfonylureas in healthy albino rabbits. 42. the tolbutamide from Albert David Ltd.[5] Lansoprazole at two dose levels – 30 mg/kg and 60 mg/kg for 7 days – significantly enhanced the duration of hypoglycemia induced by tolbutamide and the peak hypoglycemia slightly. [1.e. were procured from Sri. Blood samples were collected at the above-mentioned prefixed time intervals and blood glucose levels were estimated. esomeprazole was administered and the zero-hour blood sample was collected from all the animals of all the groups. Statistical analysis The data is presented as mean±standard error of the mean.09 mg%. 1. 3. Blood samples were collected at 0. 4. Therefore it is hypothesized that esomeprazole may influence the metabolism of study drugs. H2-receptor blockers or proton pump inhibitors are administered concomitantly with sulfonylureas or insulin preparations. and were stored under standard husbandry conditions. 24. the rats were fasted for 18 hours.[8] In the second phase.8 mg/kg and 3.6 mg/kg.5. Blood glucose levels were estimated. However. the time taken to achieve at least 20% reduction in blood glucose levels) by both the drugs was about 1 hour. and 3 were administered tolbutamide (40 mg/kg) and groups 4. The results are shown 425 . esomeprazole at doses of 1. 2..8 mg/kg. Tolbutamide 40 mg/kg and glibenclamide 40 µg/kg induced a peak hypoglycemia of 68. after 1 day of the respective sulfonylurea treatment. 8. Animals Albino rats of either sex. Bombay. The Registration No. weighing 150–250 g. were randomly distributed into 6 groups of 6 animals each. P≤0.. The experiment was conducted in two phases. the time to onset of hypoglycemia was not altered significantly. [6] Pretreatment with pantoprazole. Goa. there are no such reports regarding interactions between esomeprazole and antidiabetic agents. Experimental procedure Albino rats of either sex (150–250 g). 18. 5. On the 7th day. Zero-hour blood samples were collected for estimation of fasting blood glucose levels.e. and 3 were administered tolbutamide (40 mg/kg) and groups 4. the animals of groups 1 and 4 received esomeprazole 1. and 6 were given glibenclamide (40 µg/kg) orally. In addition. the present study planned to assess the interaction between esomeprazole and oral antidiabetic agents such as tolbutamide and glibenclamide. They were used for the study after a 7-day acclimatisation period.47±2. Similarly. Permission for the usage of animals and approval of the experimental protocols for the study was obtained from the institutional animal ethics committee prior to the experimentation.01 mg% and 70. groups 2 and 5 received esomeprazole 3.. MATERIALS AND METHODS animal house is 157/1999/CPCSEA. The time to onset of hypoglycemia (i. 36. 10 mg/kg for 7 days. RESULTS The esomeprazole used in this study was from Micro Labs Ltd. respectively.. Venkateshwara Enterprises. Analysis was by using Student’s ‘t’ test.17±2.05 is considered as statistically significant.[3] CZP2C9 is the enzyme responsible for the metabolism of phenytoin and sulfonylureas. for institutional Journal of Young Pharmacists Vol 2 / No 4 Esomeprazole 30 mg/kg per se did not alter the blood glucose levels [Figure 1]. Bangalore. and 48 hours from the tail vein of all the rats after drug treatment. The animals of groups 1. and 6 were given glibenclamide (40 µg/kg) orally. and the glibenclamide from Aventis Pharma Ltd.Drug interaction of esomeprazole and anti-diabetic drugs diabetes and peptic ulcers. 12. 2. there are reports that chronic usage of omeprazole increases the peak concentration and apparent elimination half-life of phenytoin in healthy male volunteers. increased the peak hypoglycemia and the duration of action of glipizide in healthy rabbits and rats as well as in diabetic rats.. with water supplied ad libitum. During this period the animals had free access to food and water supplied ad libitum. Bangalore.[4] One report has been published showing that proton pump inhibitors like lansoprazole induce the cytochrome-P450 enzyme system.8 mg/kg did not influence the hypoglycemia induced by tolbutamide and glibenclamide. In the first phase.

38 33.64±3.30 ± 1.00±3.70±2.44 ± 3.45±3.and glibenclamide-induced hypoglycemia was enhanced significantly by pretreatment with esomeprazole at the dose of 30 mg/kg.22 21.30 ± 5.48 25.92±4.23*** 65.0 12.0 24.6 mg/kg) + tolbutamide (40 mg/kg) Before esomeprazole After esomeprazole (mean±SEM) (mean±SEM) 18.15 52.53 68.36 22. the duration of hypoglycemia was also enhanced significantly.05 40.52 20.27±4.47 ± 5.47** 20.91 9.91±2. It may be concluded that during concomitant administration of sulfonylureas and esomeprazole at therapeutic doses.21 32. Therefore.54 Esomeprazole (3. DISCUSSION Figure 1: Blood glucose level with esomeprazole (30 mg/kg) in healthy rat in Tables 1 and 2.76 48.47 ± 3.53 57.19 19.88* 43.11** 42.85 16.82±3.18±4.[9] At the dose of 30 mg/kg esomeprazole probably inhibits these isoenzymes.45 ± 2.01* 41.58±1.47±5.22±4.08 24.84 ± 3.02±2.0 4.45 56.8 mg/kg) + tolbutamide (40 mg/kg) Before esomeprazole After esomeprazole (mean±SEM) (mean±SEM) 28.78 36.96±2.33 51.61* 67.81±1.99 17.43 59.04** 56.51 26.61 46.02±3.61±3.43±4.68±4. at 8 times the therapeutic dose.e. 30 mg/kg) on hypoglycemia induced by sulfonylureas.51±2.04 51.79 ± 4.70 59.69 65.99 29.34±2.01.99 48.30 ± 3.09 29. the therapeutic dose and the frequency of administration of sulfonylureas need not be adjusted.60±4.36 64.90±1.12±1.89±3.39 Esomeprazole (30 mg/kg) + tolbutamide (40 mg/kg) Before esomeprazole After esomeprazole (mean±SEM) (mean±SEM) 8. The literature reports reveal that sulfonylureas are metabolized mainly by CYP2C9 and CYP3A.92 29.97*** 42.44 ± 4.16± 2. Table 1: Percentage blood glucose reduction with tolbutamide in healthy albino rats before and after esomeprazole Esomeprazole (1.45 ± 1.79±1. we tried to assess the influence of more than eight times the therapeutic dose of esomeprazole (i.47±2.53±1. Similarly.22±2.78 47..27* 54.53* Fasting 0. mg% respectively.79*** 23.33* 50.32 14.0 42. Pretreatment with esomeprazole enhanced the tolbutamide induced peak hypoglycemia from 59. indicating that any interaction with antidiabetic drugs in this study is not of the pharmacodynamic type.11±3.86** 32.27±4.05±4.2(4): 424-427 160 Blood glucose level mg/100 ml 140 120 100 80 60 40 20 0 2 4 6 8 10 12 14 16 18 20 22 24 26 Time in hours from 64. et al. Since it requires eight times the therapeutic doses of esomeprazole to inhibit the CYP isoenzymes that are responsible for metabolism of sulfonylureas.42 mg% to 72.Swamy. J Young Pharm. In the present study.0 18.53±3.78 mg% to 64.59 ± 9.18 15.27±3.71 52. **Highly significant at P<0.45 ± 2.04** 36.59 9.54 61. 2010.01 56.90±4.05.52*** 52. drug–drug interaction does not occur.66*** 31.47 13.5 1.15±5.05 mg% and glibenclamide induced peak hypoglycemia Esomoprazole at 30 mg/kg dose did not by itself reduce the blood glucose level.32 20. However.53±1.10 ± 2.97±1.39±3.11±3.40** 49.20 ± 2.63±3.0 8.76 ± 3. Tolbutamide.37±2.05** 53.59 37.72±4.77 10.0 *Significant at P<0.93 ± 2.34±3.18±3.0 2.55±2.0 6.58±3.36** 68. The pilot studies showed no influence of pretreatment with esomeprazole (up to 20 mg/kg) on the hypoglycemia induced by oral tolbutamide and glibenclamide.17±2.66±3.99±5.82 30. these enzymes apparently have low sensitivity/affinity for esomeprazole.37±4. Therefore.43 28. esomeprazole enhanced the duration of hypoglycemia as well as the peak level of hypoglycemia induced by sulfonylureas.17 59.93.08±1. therapeutic doses of esomeprazole did not influence any of the parameters of the hypoglycemia induced by sulfonylureas.10* 59.0 48.28±2.0 36. The results are compiled in.62 33.46±2. ***Very highly significant at P<0.44 39.94 ± 1.78 42.29±2.001 426 Journal of Young Pharmacists Vol 2 / No 4 .56** 43.18 8.78±5.73±1.87 ± 3.42 36.76 24.57* 33.93 27.90 50.70 43.50 34.79±3.57 ± 2.17±4.40±4.07 ± 3.0 30.

39 ± 1.16±2.97±1.66±3.01 ***Very highly significant at P<0.45* 33. 1996.02 52. Source of Support: TMAE society and the SCS college of Pharmacy. Metabolic interactions of the proton pump inhibitors lansoprazole.58 8.07±3.42 58.54±3.92 16.26 ± 2. Influence of lansoprazole on hypoglycaemic activity of oral antidiabetic agents in healthy albino rats.40 29.51 60. Trinder P.05 16.79±1.90 42.58 ± 2. 901-15. Babitha S. 2005. for providing basic facilities and financial assistance.87±3. Antal AL.93 50.11 ± 1.55* 52.09 69. Kubacka KJ. Journal of Young Pharmacists Vol 2 / No 4 427 .36±1.0 6. A study on the drug-drug interaction of pentaprazole with glipizide.57** 44.96±3. Insulin. Melander A.90 25.70±2. albino rabbits. p.35** 23. 4. Davis SN.49±4.63±2.0 36.65 70.39±3. 2.01*** 66. Rajendra SV.16±0.62 29.98±5.52** − 72.8 mg/kg) + glibenclamide Esomeprazole (3. p.28 32.46 8.78 44. Eur J Gastroenterol Hepatol 1996.77±3.53 20. Kitchingman GK.38±3. Concentration effect relations of glibenclamide and its active metabolites in man: Modeling of pharmacokinetics and pharmacodynamics. 9.72 ± 1.77±4. Harapanahalli. Langman MJ. et al.64±4.29 ± 3.34±2.0 18.19 16.97 60.87 36. Limbird LE.62±3. Kumar V.62±5.43:373-81.04*** 64.Drug interaction of esomeprazole and anti-diabetic drugs Table 2: Percentage blood glucose reduction with glibenclamide in healthy albino rats before and after esomeprazole Esomeprazole (1. 7.06±2.84* 56.0 8. Rydberg T.80 ± 3.05±4.46:95-9.0 2. Joshi VG.91±1. 6.00 64. Venkatrao N.04±1.5 1.85±4.59 35.78 38.60±4.66** 43.39 13. 252.68±2. 9th ed.76** 58.17±2.92±2. Determination of glucose in blood using glucose oxidase with an alternative oxygen receptor.72 57.6 mg/kg) + glibenclamide Esomeprazole (30 mg/kg) + glibenclamide (40 µg /kg) (40 µg /kg) (40 µg /kg) Before esomeprazole After esomeprazole Before esomeprazole After esomeprazole Before esomeprazole After esomeprazole (mean ± SEM) (mean ± SEM) (mean ± SEM) (mean ± SEM) (mean ± SEM) (mean ± SEM) 28.18±2. omeprazole and pentaprazole with other drugs.51±3. Ann Clin Biochem 1969.001 ACKNOWLEDGMENTS The authors are highly indebted to the management of TMAE society and the SCS college of Pharmacy.55 40.95 31.42:135-8. Oral phenytoin phrmacokinetics during omeprazole therapy. oral hypoglycaemic agents and pharmacology of endocrine pancreas.53 29. Ramachandra Setty S. Harapanahalli.05±5. Acta Pharmaceutica Turcica 2004.93±4.71±4.80±8. Paradoxical effects of cimetidine and ranitidine on glibenclamide pharmacokinetics and pharmacodynamics.94 44.74±1.02±1.03 21.93 65.80 52.56 42. editors.71 ± 3.40 68.0 42.0 48. Br J Clin Pharmacol 1987.75±2.35±3.68±1.09 58.35 17. Goodman and Gilman’s the pharmacological basis of therapeutics. Acta Pharm Turc 2000.8:521-5. Juhl RP.16 38.23:743-51.86±1. Somerville KW.85** 70. Williams J. Meyer UA.07±5.05.73 11. Wait RP. Br J Clin Pharmacol 1997.40 − 68.43±9.86 51.24:543-5. Swamy S. Raghaveergupta PS.60±3. Venakat Rao N.25±2.61±3.59 60.16 45. Karegouda GL. Prichard PJ.0 24. NewYork: Megraw-Hill.84±4.49±2. Br J Clin Pharmacol 1987.05±2.0 12.06±2. REFERENCES 1.35 ± 2.06* 57.91±4.11 ± 3.65 37.41 25.29±5. Granner DK.6:24-7.72 33.75*** 46.36± 5.49±3.79 45.33±9.39*** 53.80 47.91*** 55. In: Hardman JG.20 21. **Highly significant at P<0.56±3.20*** Fasting 0.59 49.19*** 31.57 13. Jonsson A. Karlsson MO.68±1.20 ± 1. Hyderabad: 57th Ind Pharm Congress.0 30. 3.81 42.97±3.52±0.32 ± 2.69±1.99 29.73±3. Influence of omeprazole on hypoglycaemic activity of glibenclamide and tolbutamide in normal 5.02 27.21 58.30 55.0 4.0 *Significant at P<0.44*** 58.72 38. Ramachandra Setty S.41* 67. Conflict of Interest: None declared.73 20.14 ±2. 8. Anand Kumar Y. Gilman AG.