Reporting of Phenytoin (Dilantin) Concentration

Reporting of Phenytoin (Dilantin) Concentration

In an attempt to remind clinicians of the importance of the degree of protein binding in the action of phenytoin and in the interpretation of serum/plasma phenytoin concentrations, the Clinical Laboratories of John Muir Health will soon report two additional "corrected" phenytoin concentration calculations when serum/plasma albumin falls below 4.0 mg/dL. The rationale for the "corrected" values relates to changes in the bound vs. unbound fractions as explained below.

As a review, phenytoin (diphenylhydantoin) acts by modulating the synaptic sodium channel by prolonging inactivation, which reduces the ability of the neuron to respond at high frequency. The physiologic effect of this action is reduction in central synaptic transmission, aiding in control of abnormal neuronal excitability. The optimal therapeutic concentration for seizure control is 10-20 µg/mL. Total phenytoin concentrations >20 µg/mL do not usually enhance seizure control and are often associated with nystagmus and ataxia. Concentrations >35 µg/mL have been shown to actually precipitate seizure activity. Development of gingival hyperplasia, a side effect of phenytoin, does not appear related to serum/plasma concentration.

Once absorbed, phenytoin is tightly bound to protein (90-95%) and has a half-life around 20 hours. As with all drugs, the pharmacological effect is directly related to the amount present in the free (unbound) state. Only free phenytoin is available to cross biological membranes and interact at biologically important binding sites. The degree of protein binding can be reduced by hypoalbuminemia, uremia, and by the presence of other drugs that compete for protein-binding sites (e.g. salicylate, valproic acid, sulfisoxazole and sulfonylureas). In these conditions, an increased effect is observed (due to increased free form) at the same total drug concentration as in serum/plasma from normal patients. Virtually all phenytoin assays commercially available measure total phenytoin concentration. Unfortunately, the measurement of free phenytoin is challenging and not readily available in house, thus not available in a timely fashion.

The Clinical Laboratories will utilize two equations that have been shown to be useful in predicting free phenytoin concentration in patients with hypoalbuminemia (defined as <4.0 mg/dL) and normal function and those with renal failure (Creatinine Clearance <10mL/min).

For normal renal function: For renal failure:
Corrected phenytoin = Measured total phenytoin
(0.2 x Albumin) + 0.1
Corrected phenytoin = Measured total phenytoin
(0.1 x Albumin) + 0.1

To help the Clinical Laboratory assist you in this patient safety initiative, we ask that an Albumin be ordered whenever Phenytoin concentration is desired.

The foregoing has been endorsed by the Pharmacy and Therapeutics Committees of John Muir Health. If there are any questions or concerns, please do not hesitate to contact me. Thank you.

References

Evans WE, et al. Applied Pharmacokinetics: Principles of Therapeutic Drug Monitoring. Vancouver: Applied Therapeutics. 1992.

Winters ME. Basic Clinical Pharmakokinetics. Vancouver: Applied Therapeutics. 1994.