Lipid lowering inefficacy of high-dose statin therapy due to concurrent use of phenytoin.

Abstract: HMG-CoA reductase inhibitors ("statins") are the most commonly prescribed lipid lowering agents. Most of the statins are metabolized by the CYP450 cytochrome system. A number of medications either induce or inhibit this system which leads to changes in the bioavailability of the statins and the potential for either an increase in adverse effects or reduction in efficacy. Phenytoin induces the CYP3A4 isoform of the CYP450 system and can reduce the bioavailability, and thus the efficacy of the statins metabolized by this enzyme, including atorvastatin and lovastatin. A case of a patient on multiple lipid-lowering medications, including high-dose atorvastatin whose LDL cholesterol improved significantly after discontinuation of phenytoin is presented, and a review of the literature for similar cases is discussed.

Key Words: CYP450, epilepsy, dyslipidemia, hypolipidemic agents, antiseizure medications

Case Report

A 61-year-old male was referred for further assessment of dyslipidemia. His past medical history was significant for coronary artery disease, CABG at the age of 47, epilepsy, dyslipidemia and hypertension. He was asymptomatic at the time of assessment and the physical examination was unremarkable; specifically, there were no xanthelasmas, xanthomas, carotid or peripheral bruits. His family history was significant for hypercholesterolemia in his father. There was no history of premature CAD. His medications included aspirin 81 mg, fosinopril 20 mg/d, phenobarbital 200 mg/d and phenytoin 500 mg/d. To his recollection, he had been on the same antiseizure medications for at least ten years. His lipid profile at the time of assessment was as follows: total cholesterol (TC) 330 mg/dL, LDL 256 mg/dL, HDL 38 mg/dL, triglycerides (TG) 195 mg/dL. He was compliant with his medications and diet, and denied alcohol abuse. There was no clinical or biochemical evidence of liver, renal or thyroid disease to suggest a secondary cause of dyslipidemia.

A diagnosis of familial hypercholesterolemia was made and given the significantly elevated LDL, it was decided to initiate treatment with atorvastatin 40 mg/d. The patient tolerated his medications without any side effects and denied any myalgias. His repeat lipid profile after eight weeks demonstrated a TC of 287 mg/dL, LDL 205 mg/dL, HDL 39 mg/dL and TG 210 mg/dL. As the LDL was still above target, the dose of atorvastatin was increased to 80 mg/d; in addition, ezetimibe 10 mg was added along with niacin; the dose of the latter was gradually increased to 2 g/d. The lipid profile on triple therapy for ten weeks was as follows: TC 246 mg/dL, LDL 165 mg/dL, HDL 55 mg/dL and TG 130 mg/dL. The patient subsequently had PTCA following an acute coronary event and it was decided to discontinue the niacin and continue with atorvastatin and ezetimibe. A lipid profile two months later demonstrated a TC of 288 mg/dL, LDL 225 mg/dL, HDL 38 mg/dL and TG 124 mg/dL; the niacin was subsequently restarted. Given the lack of significant response to multiple lipid-lowering therapy, including a high dose of a potent statin, it was postulated that the phenytoin was affecting the bioavailability of the antilipidemic agents, particularly atorvastatin. As the patient had been seizure-free for over 15 years, it was decided, after consultation with the patient's neurologist, to discontinue the phenytoin. The patient continued with triple therapy for dyslipidemia and his repeat lipid profile two months after discontinuing the phenytoin demonstrated a TC of 190 mg/dL, LDL 110 mg/dL, HDL 55 mg/dL, and TG 130 mg/dL. The time course of his lipid profile and concurrent lipid-lowering medications are depicted in the Figure. Although his LDL currently remains above target on three lipid-lowering agents, it was reduced by about 50% after discontinuing phenytoin. To date, the patient has remained seizure-free for six months on phenobarbital monotherapy.

Discussion

HMG-CoA reductase inhibitors ("statins") are the most widely used lipid lowering agents and in addition to their LDL-lowering effect and reduction in cardiovascular morbidity and mortality, they also have additional beneficial effects due to their pleiotropic effects on the endothelium, plaque stabilization, etc. (1,2) Most of the statins are metabolized by the cytochrome P450 system. (3) The super family CYP450 is further divided into subfamilies depending on the degree of homology in amino acid sequences between the isozymes. Over 70 CYP families have been identified to date. Of the various subfamilies, the CYP2C, CYP2D and CYP3A subfamilies are involved in the metabolism of the most commonly prescribed drugs. The CYP3A subfamily is the most abundant, followed by CYP2C subfamily and CYP2D. The major isozyme of the CYP3A subfamily is CYP3A4 and over 150 drugs are substrates of this enzyme. The inhibitors of the CYP enzymes would be expected to increase the concentration of its substrates and cause the potential for adverse effects, whereas inducers of the enzyme would be expected to lead to subtherapeutic drug levels resulting in reduced efficacy. Although the list of inhibitors and inducers of the CYP enzymes is extensive, commonly used medications that inhibit the CYP enzymes include the macrolide antibiotics, cimetidine, antiretroviral agents, azole antifungal agents (ketoconazole, itraconazole, and fluconazole), cyclosporine, grapefruit juice, etc. (4-6) Common inducers of the CYP enzymes include phenytoin, phenobarbital, carbamazepine, rifampin and alcohol. (7)

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When statin therapy is prescribed, the major clinical concern is the increased risk of rhabdomyolysis associated with their use, particularly if any medications that inhibit the CYP system are used concomitantly. (8) Of the various available statins, lovastatin, simvastatin and atorvastatin are substrates of CYPA34 and thus would be subject to inhibition of metabolism by concomitant use of various agents that inhibit the system. (9) Cerivastatin, which has been withdrawn, is also a substrate of CYPA34. (10) Fluvastatin is metabolized primarily by CYP2C9 and this enzyme is inhibited weakly by agents such as ritonavir, cimetidine and azole antifungals. (3) Pravastatin, on the other hand, is not metabolized by the CYP system and therefore its pharmacokinetics would not be expected to be significantly altered by concomitant use with inhibitors or inducers of CYP. (3) Rosuvastatin is not extensively metabolized but has some interaction with the CYP2C9 enzyme. (11) Phenytoin, phenobarbital and rifampin induce all of the CYP enzymes and thus carry the potential of lowering the availability of various drugs metabolized by the system. (12) It also needs to be appreciated that there may be significant interindividual variability in the extent of drug interactions, as CYP enzymes show genetic polymorphisms which may result in significant variability of drug metabolizing capabilities. In the future, genotyping of these enzymes should provide invaluable information and minimize the risk of drug-drug interactions. (13)

In the case presented, the patient's LDL level remained significantly elevated despite the use of three antilipidemic agents. In general, one would expect up to a 60% reduction in LDL from baseline with 80 mg of atorvastatin; adding ezetimibe would be expected to lead to a further 15 to 20% reduction in LDL, and niacin would lead to further lowering of LDL by another 15 to 30%. Yet, the patient's LDL was reduced by <40% from baseline despite three agents. However, after discontinuing the phenytoin, the LDL was further reduced significantly to 110 mg/dL. Although phenytoin was not reintroduced at a later date to demonstrate the reversal of the beneficial effect that was seen upon its discontinuation, it is felt that the circumstantial evidence presented in this case is enough to strongly suggest a cause and effect relationship. Theoretically, pravastatin or perhaps rosuvastatin could have provided greater LDL-lowering effect in the presence of phenytoin, because of their lack of metabolism by the CYP450 system; this however was not attempted. Although it was appreciated that the patient was on phenobarbital which also induces CYP450 and could have reduced the bioavailability of atorvastatin, it was decided by the author, based on a published case report, (12) to discontinue phenytoin initially. This was in concert with the neurologist's recommendation as well.

This case illustrates an important drug interaction of the statin class of medications. Cases of rhabdomyolysis associated with various statins due to concomitant use of drugs inhibiting the CYP450 systems have been widely reported in the literature; however, reduction in the efficacy of statins due to use of inducers of the CYP450 is not well appreciated. The author is aware of one other case report demonstrating a similar effect of phenytoin on the pharmacokinetics of simvastatin and atorvastatin. (12) It is believed that this case will highlight and provide further insight into the drug interactions of this important and commonly prescribed class of medications. It is suggested that in patients on medications such as phenytoin whose lipid levels remain significantly elevated on statins, consideration should be given to either discontinuing the antiseizure medication if it is deemed safe to do so, or switching to an antiseizure medication which does not induce the CYP450 system. If the antiseizure medications cannot be switched, using statins which are not metabolized by CYP3A4, such as fluvastatin, pravastatin or rosuvastatin instead of atorvastatin can be tried.

References

1. Wiviott SD, de Lemos JA, Cannon CP, et al. A tale of two trials: a comparison of the post-acute coronary syndrome lipid-lowering trials A to Z and PROVE IT-TIMI 22. Circulation 2006;113:1406-1414.

2. Ray KK, Cannon CP. Early time to benefit with intensive statin treatment: could it be the pleiotropic effects? Am J Cardiol 2005;96:54F-60F.

3. Williams D, Feely J. Pharmacokinetic-pharmacodynamic drug interactions with HMG-CoA reductase inhibitors. Clin Pharmacokinet 2002;41:343-370.

4. Piacentini N, Trifiro G, Tari M, et al. Statin-macrolide interaction risk: a population-based study throughout a general practice database. Eur J Clin Pharmacol 2005;61:615-620.

5. Fichtenbaum CJ, Gerber JG. Interactions between antiretroviral drugs and drugs used for the therapy of the metabolic complications encountered during HIV infection. Clin Pharmacokinet 2002;41:1195-1211.

6. Maxa JL, Melton LB, Ogu CC, et al. Rhabdomyolysis after concomitant use of cyclosporine, simvastatin, gemfibrozil, and itraconazole. Ann Pharmacother 2002;36:820-823.

7. Bellosta S, Paoletti R, Corsini A. Safety of statins: focus on clinical pharmacokinetics and drug interactions. Circulation 2004;109(23 Suppl 1):III-50-III-57.

8. Silva MA, Swanson AC, Gandhi PJ, et al. Statin-related adverse events: a meta-analysis. Clin Ther 2006;28:26-35.

9. Lennernas H. Clinical pharmacokinetics of atorvastatin. Clin Pharmacokinet 2003;42:1141-1160.

10. Muck W. Clinical pharmacokinetics of cerivastatin. Clin Pharmacokinet 2000;39:99-116.

11. Rosenson RS. Rosuvastatin: a new inhibitor of HMG-coA reductase for the treatment of dyslipidemia. Expert Rev Cardiovasc Ther 2003;4:495-505.

12. Murphy MJ, Dominiczak MH. Efficacy of statin therapy: possible effect of phenytoin. Postgrad Med J 1999;75:359-360.

13. Lee LS, Nafziger AN, Bertino JS Jr. Evaluation of inhibitory drug interactions during drug development: genetic polymorphisms must be considered. Clin Pharmacol Ther 2005;78:1-6.

Hasnain M. Khandwala, MD, FRCPC 

From the Division of Endocrinology, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.

Reprint requests to Hasnain M. Khandwala, MD, FRCPC, LMC Endocrinology Centers, 412-1235 Trafalgar Road, Oakville, ON, Canada L6H 3P1. Email: [e-mail]

Accepted July 10, 2006.

RELATED ARTICLE: Key Points

* HMG-CoA reductase inhibitors ("statins") are the most commonly prescribed lipid-lowering agents and most of them (atorvastatin, cerivastatin, lovastatin, simvastatin) are metabolized by the CYP3A4 isoform of the CYP450 cytoehrome system.

* Phenytoin induces the CYP450 system and can reduce the bioavailability and thus the efficacy of statins.

* Physicians should be aware of the interaction between statins and phenytoin and consider either discontinuing the antiseizure medication if possible, or instituting agents which do not induce the CYP450 system.