Abstract

Drug interactions between phenytoin and rosuvastatin may occur when used together in normal rats, so the present study was conducted to investigate the effects of the individual as well as combined drugs were studied in normal rats. Rats were divided into 4 groups namely: normal control, phenytoin (60 mg/kg i.p.), rosuvastatin (1.25 mg/kg i.p.) or combination of both phenytoin and rosuvastatin, respectively. Data of the present work revealed that, phenytoin increased serum total cholesterol. Rosuvastatin didn’t affect serum total cholesterol or serum triglycerides. Combination increased serum total cholesterol but it didn’t affect serum triglycerides. Phenytoin significantly increased serum LDL-C. Rosuvastatin had no effect on serum HDL-C, serum LDL-C and VLDL-C levels. Combination didn’t change serum lipoproteins (HDL-C, LDL-C and VLDL-C). Individual drugs or their combination had no effect on risk factor and atherogenic index. Phenytoin significantly increased serum ALT level. Rosuvastatin had no effect on serum AST and serum ALT levels. Combination significantly increased serum AST level. Phenytoin significantly increased serum MDA level but it had no effects on serum NO level and blood SOD activity. Rosuvastatin significantly increased serum NO level. Combination significantly increased serum NO level, so Combination of phenytoin and rosuvastatin has a good effect on oxidative stress by increasing serum NO level. In conclusion, the results revealed that, there are drug interactions between phenytoin and rosuvastatin. The interactions improve liver functions and lipid peroxidation. A part from the action of the combination on total cholesterol, it improves lipid profile.

Keywords:

Antiepileptic, drug interaction, lipid profile, liver functions, oxidative stress biomarkers, statins,

References

1. Ansari, J.A., U. Bhandari, K.K. Pillali and S.E. Haque, 2012. Effect of rosuvastatin on obesity-induced cardiac oxidative stress in Wistar rats-a preliminary study. Indian J. Exp. Biol., 50: 216-222.
   PMid:22439437    
2. Arnold, K., N. Geber and G. Levy, 1970. Absorption and dissolution studies on sodium diphenylhydantoin capsules. Can. J. Pharm. Sci., 5: 89-92.
   
3. Balci, F., D. Freestone and C.R. Gallistel, 2009. Risk assessment in man and mouse. P. Natl. Acad. Sci. USA, 106: 2459-2463.
   CrossRef    PMid:19188592 PMCid:PMC2634808    
4. Bavdekar, S.B., M.N. Muranjan, N.J. Gogtay, V. Kantharia and N.A. Kshirsagar, 2004. Anticonvulsant hypersensitivity syndrome: Lymphocyte toxicity assay for the confirmation of diagnosis and risk assessment. Ann. Pharmacother., 38: 1648-1650.
   CrossRef    PMid:15304627    
5. Blasetto, J.W., E.A. Stein, W.V. Brown, R. Chitra and A. Raza, 2003. Efficacy of rosuvastatin compared with other statins at selected starting doses in hypercholesterolemic patients and in special population groups. Am. J. Cardiol., 91(5A): 3-10.
   CrossRef    
6. Cadenas, E. and K.J. Davies, 2000. Mitochondrial free radical production, oxidative stress and aging. Free Radical Bio. Med., 29: 222-223.
   CrossRef    
7. Cheng, W.M., 2004. Rosuvastatin in the management of hyperlipidemia. Clin. Ther., 26(9): 1368-1387.
   CrossRef    PMid:15531000    
8. Edmonds, H.L., L.G. Stark and M.A. Hollinger, 1974. The effects of diphenylhydantoin, Phenobarbital and diazepam on the penicillin-induced epileptogenic focus in the rat. Exp. Neurol., 45: 377-386.
   CrossRef    
9. Endo, A., Y. Tsujita, M. Kuroda and K. Tanzawa, 1979. Effects of ML-236B on cholesterol metabolism in mice and rats: Lack of hypocholesterolemic activity in normal animals. Biochim. Biophys. Acta, 575: 266-276.
   CrossRef    
10. Finkel, T. and N.J. Holbrook, 2000. Oxidants, oxidative stress and the biology of ageing. Nature, 408: 239-247.
    CrossRef    PMid:11089981    Direct Link
11. Fossati, P. and L. Prencipe, 1982. Serum triglycerides determined colorimetrically with an enzyme that produces hydrogen peroxide. Clin. Chem., 28(10): 2077-2080.
    PMid:6812986    
12. Friedewald, W.T., R.I. Levy and D.S. Fredrickson, 1972. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin. Chem., 18: 499-502.
    PMid:4337382    
13. Geng, J.T., Q. Wu and K. Hansson, 1994. Protein kinase C activation inhibits cytokine-induced nitric oxide synthesis in vascular smooth muscle cells. Biochim. Biophys. Acta, 223:125-132.
    CrossRef    
14. Itemobong, S., M.I. Ekaidem, I. Monday, Akpanabiatu, E. Friday and U. Offiong, 2007. Effect of folic acid and vitamin B(12) administration on phenytoin induced toxicity in rats. Indian J. Clin. Biochem., 22(2): 36-40.
    CrossRef    PMid:23105679 PMCid:PMC3453800    
15. Jones, P.H., M.H. Davidson, E.A. Stein, H.E. Bays, J.M. McKenney, E. Miller, V.A. Cain and J.W. Blasetto, 2003. Comparison of the efficacy and safety of rosuvastatin versus atorvastatin, simvastatin and pravastatin across doses (STELLAR* Trial). Am. J. Cardiol., 92: 152-160.
    CrossRef    
16. Lalonde, R. and M.I. Botez, 1958. Subsensivity to muscimol-induced catalepsy after long-term administration of phenytoin in rats. Psychopharmacol., 86: 77-80.
    CrossRef    
17. Laufs, U., V. La Fata, J. Plutzky and J.K. Liao, 1998. Upregulation of endothelial nitric oxide synthase by HMG CoA reductase inhibitors. Circulation, 97:1129-1135.
    CrossRef    PMid:9537338    
18. Liu, J.R., S.Y. Wang, M.J. Chen, H.L. Chen, P.Y. Yuerh and C.W. Lin, 2006. Hypocholesterolaemic effects of milk-kefir and soyamilk-kefir in cholesterol-fed hamsters. Brit. J. Nutr., 95: 939-946.
    CrossRef    PMid:16611384    
19. Lopes-Virella, M.F., P. Stone, S. Ellis and J.A. Colwell, 1977. Cholesterol determination in high-density lipoproteins separated by three different methods. Clin. Chem., 13(4): 285-291.
    
20. Luoma, P.V., M.I. Reumanen and E.A. Sofaniemi, 1979. Changes in serum triglyceride and cholesterol levels during long-term phenytoin treatment for epilepsy. Acta Med. Scand., 206: 229-231.
    CrossRef    PMid:495231    
21. Marnett, L.J., 2000. Oxyradicals and DNA damage. Carcinogenesis, 21: 361-370.
    CrossRef    PMid:10688856    
22. Minaiyan, M., T. Ghafghazi and M. Majdzadeh-Ardakani, 2008. Study of pharmacokinetic interaction of ascorbic acid and phenytoin in rats. DARU, 16(2): 70-75.
    
23. Minami, M. and H. Yoshikawa, 1979. A simplified assay method of superoxide dismutase activity for clinical use. Clin. Chim. Acta, 92(3): 337-342.
    CrossRef    
24. Olteanu, D., A. Nagy, M. Dudea, A. Filip, A. Muresan, C. Catoi, P.A. Mircea and S. Clichici, 2012. Hepatic and systemic effects of rosuvastatin on an experimental model of bile duct ligation in rats. J. Physiol. Pharmacol., 63(5): 483-496.
    PMid:23211302    
25. Pincus, J.H. and S. Lee, 1973. Diphenylhydantoin and calcium. Arch. Neurol., 26: 239-244.
    CrossRef    
26. Potsalos, P.N., W. Froscher, F. Pisani and C.M. Van Rigin, 2002. The importance of drug interactions in epilepsy therapy. Epilepsia., 43: 365-385.
    CrossRef    
27. Potter, P.E., P. Detwiller, B. Thorne and J.R. Moskal, 1991. Diphenylhydantoin attenuates hypoxia-induced release of [3H]glutamate from rat hippocampal slices. Brain Res., 558: 127-130.
    CrossRef    
28. Preusch, M.R., A. Vanakaris, F. Bea, N. Ieronimakis, T. Shimizu, M. Konstandin, S. Morris-Rosenfeld, C. Albrecht, A. Kranzhofer, H.A. Katus, E. Blessing and R. Kranzhofer, 2010. Rosuvastatin reduces neointima formation in a rat model of balloon injury. Eur. J. Med. Res., 15: 461-467.
    CrossRef    PMid:21159570 PMCid:PMC3352654    
29. Rec. GSCC., 1972. Deutsche gesellschaft fur klinische chemie. J. Clin. Chem. Clin. Biochem., 10: 182.
    
30. Reitman, S. and S. Frankel, 1957. A colorimetric method for the determination of serum glutamic oxalacetic and glutamic pyruvic transaminases. Am. J. Clin. Pathol., 28(1): 56-63.
    CrossRef    PMid:13458125    
31. Richmond, W., 1973. Preparation and properties of a cholesterol oxidase from No cardia sp. and its application to the enzymatic assay of total cholesterol in serum. Clin. Chem., 19(12): 1350-1356.
    PMid:4757363    
32. Rodrigo, N.F., N.R. Vinicius, S.M. Vanessa, A.M. Carlos and C. Jorge Jose, 2013. Pleiotropic effects of rosuvastatin on the glucose metabolism and the subcutaneous and visceral adipose tissue behavior in C57B1/6 mice. Diabet. Metab. Syn., 5:1-32.
    
33. Santosa, N.A., W.S. Medinaa, N.M. Martinsa, F.E. Mingattob, C. Curtic and A.C. Santos, 2008. Aromatic antiepileptic drugs and mitochondrial toxicity: Effects on mitochondria isolated from rat liver. Toxicol. Vitro, 22: 1143-1152.
    CrossRef    PMid:18434079    
34. Stadtman, E.R. and R.L. Levine, 2000. Protein oxidation. Ann. Ny. Acad. Sci., 899: 191-208.
    CrossRef    PMid:10863540    
35. Takagi, H. and T. Umemoto, 2012. Atorvastatin reduces coronary plaque volume in dependence on reductions in low-density lipoprotein: A meta-analysis and meta-regression of randomized controlled trials. Int. J. Cardiol., 157:114-116.
    CrossRef    PMid:22341753    
36. Timothy, J.S., M.L. Allan and S. Rosario, 2001. A new HMG-CoA reductase inhibitor, rosuvastatin, exerts anti-inflammatory effects on the microvascular endothelium: The role of mevalonic acid. Brit. J. Pharmacol., 133: 406-412.
    CrossRef    PMid:11375257 PMCid:PMC1572789    
37. Woodbury, D., J. Penry and C. Pippenger, 1982. Anti-epileptic Drugs. Raven Press, New York. pp: 663-671.
    
38. Ying, Y., M. Yun, H.U. Shen-Jiang and F.U. Michael, 2009. Beneficial effect of rosuvastatin on cardiac dysfunction is associated with alterations in calcium-regulatory proteins. Eur. J. Heart. Fail., 11: 6-13.
    CrossRef    PMid:19147451    
39. Ylä-Herttuala, S., 1999. Oxidized LDL and atherogenesis. Ann. Ny. Acad. Sci., 874: 134-137.
    CrossRef    PMid:10415527    
40. Yoshioka, T., K. Kawada, T. Shimada and M. Mori, 1979. Lipid peroxidation in maternal and cord blood and protective mechanism against activated-oxygen toxicity in the blood. Am. J. Obstet. Gynecol., 135(3): 372-376.
    CrossRef    

Competing interests

The authors have no competing interests.

Open Access Policy

This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

Copyright

The authors have no competing interests.