Statins and phenytoin interact – a case history

Phenytoin and a number of statins are metabolized by the superfamily of cytochrome P450 (CYP) isoenzymes present in the intestines, liver, lung, kidney and brain. This leads to the possibility of pharmacokinetic drug interactions, given the well-known enzyme-inducing properties of phenytoin. The present clinical case illustrates the potential for an altered dose of an inducing agent to produce important pharmacodynamic effects. In addition, one should not overlook the possibility of a contribution by a mechanism not involving cytochrome P450.

A 78-year-old female patient was admitted through the Emergency Department with truncal ataxia. She was found to have phenytoin toxicity (serum phenytoin 38.6 µg ml⁻¹). She had a history of hypertension, hypercholesterolaemia, atherosclerotic unilateral renal artery stenosis and generalized tonic-clonic seizures due to cerebrovascular atherosclerotic disease.

Her condition had been stabilized on bisoprolol 5 mg, bendrofluazide 2.5 mg, aspirin 75 mg, simvastatin 40 mg and phenytoin 300 mg daily for the previous several years. Frequent therapeutic drug monitoring of her serum phenytoin revealed the levels to be in the therapeutic range at 12.7 µg ml⁻¹ (therapeutic 10–20 µg ml⁻¹). Following statin therapy, her total random serum cholesterol dropped from 8.0 mmol l⁻¹ to an average of 5.6 mmol l⁻¹.

On this occasion, history taking revealed that she had inadvertently taken extra phenytoin 300 mg daily for 1 week instead of her bendrofluazide tablet, while continuing her regular statin therapy. This was confirmed by tablet counting. At the same time serum cholesterol was measured at 8.0 mmol l⁻¹. During hospitalization, phenytoin therapy was withheld and her symptoms resolved. Her simvastatin therapy was continued at the same dosage of 40 mg daily. Serum phenytoin monitoring revealed a gradual reduction in the phenytoin levels and in her serum cholesterol levels (Figure 1).

Figure 1.

Relationship between phenytoin and cholesterol levels. (, Phenytoin; , Cholesterol)

At discharge, phenytoin levels fell to 11.7 µg ml⁻¹. Her phenytoin was re-introduced at her previous dosage level and 22 days after admission her serum phenytoin was in the therapeutic range at 15.0 µg ml⁻¹ and her cholesterol was 6.2 mmol l⁻¹. She was kept under review and 1 year after admission, her phenytoin level was therapeutic at 14.6 µg ml⁻¹ and her cholesterol level 5.6 mmol l⁻¹.

Simvastatin is metabolized by the CYP3A4 isoenzyme together with atorvastatin [1], but on the other hand pravastatin is not extensively metabolized by the cytochrome P450 system [1]. Phenytoin, which itself is metabolized by the CYP2C9 and 2C19 isoenzymes [2], is a known inducer of the CYP3A4 isoenzyme [3]. This has the potential to cause a reduced serum level of simvastatin leading to an increase in cholesterol level. In the present case, it is possible that pravastatin would have been a more appropriate cholesterol-lowering agent.

A further possible source of interaction could involve P-glycoprotein, an ATP-dependent drug transport protein in the intestinal plasma membrane. P-glycoprotein can also be found in cells of other organs including the liver, kidneys and central nervous system. Phenytoin has been shown to be an inducer of P-glycoprotein [4]. Simvastatin is a substrate for as well as an inhibitor of P-glycoprotein [1].

There is coordination between the CYP3A4 isoenzyme and P-glycoprotein in the plasma membrane of the intestine. A drug entering the intestinal epithelium may be effluxed (pumped) back into the intestine via P-glycoprotein or metabolized by CYP3A4 with the inactive drug absorbed across the epithelium [5]. The drug effluxed by P-glycoprotein is subject to having this process repeated, resulting in additional drug metabolism by intestinal CYP3A4 [5]. However, there is insufficient information at present to quantify any contribution of this putative mechanism, although it is worth noting that verapamil, which is a well-documented inhibitor of P-glycoprotein, can increase simvastatin concentrations considerably [6].

Phenytoin is not listed as a substance that can interact with the cholesterol assay used in our laboratory [7]. Two previous studies have also found that phenytoin does not significantly increase levels of total cholesterol in humans [8, 9]. The rapid increase in serum cholesterol level may be related to rapid regeneration of the 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase enzyme in the presence of a reduced level of simvastatin.

A case report published in 1999 showed similar observations following a switch from sodium valproate to phenytoin [10]. The present case further demonstrates the interaction between simvastatin and phenytoin leading to therapeutic failure of the statin, and illustrates the rapid effect of the increased concentration of phenytoin on levels of total cholesterol as well as the rapid return of cholesterol to previous steady-state levels correlating with therapeutic phenytoin levels. This case also illustrates the significant consequences of changing the dose of an interacting agent in a patient in whom treatment is stabilized, something easily overlooked by a prescriber.

It is vital that prescribers understand the fundamental pharmacodynamics and pharmacokinetics of medication in general, in particular the large number of drugs that undergo metabolism by the cytochrome P450 system. Access to the relevant information will reduce risks to patients.