Should we routinely measure free plasma phenytoin concentration?

Abstract

The plasma protein binding of phenytoin was investigated in 56 epileptic patients attending the outpatient clinc. The free phenytoin fraction was measured by equilibrium dialysis at 37°C and the total concentration by a homogenous enzyme immunoassay technique. The free fraction ranged from 0.123 to 0.177 (median 0.144, mean + s.d. = 0.145 + 0.012). Distribution was consistent with normality. Four of the patients were also taking sodium valproate. The median free fraction of phenytoin in these patients was 0.174, 21% higher than that of the total group (P < 0.05).The total concentration of phenytoin varied from 0.3 to 29.4 4g/ml (median 12 ,ug/ml, mean + s.d. = 13.31 + 6.13 ,g/ml) and the free fraction was not related to the total drug concentration. There was a highly significant relationship between free phenytoin concentration and total phenytoin concentration (r = 0.986, P < 0.001). There appears to be very little variability in protein binding of phenytoin in epileptic patients and thus total plasma phenytoin concentration closely reflects the free (unbound) drug concentration. Routine estimation of free plasma phenytoin concentration is therefore unnecessary and should be reserved for those patients where alteration in binding is likely, e.g. renal or hepatic disease or where adverse effects occur at unexpectedly low total phenytoin concentrations.

Influence of CYP2C9 Genetic Polymorphism and Undernourishment on Plasma-Free Phenytoin Concentrations in Epileptic Patients

“…Routine monitoring of total plasma PHT concentrations helps clinicians in optimizing the treatment of epileptic patients. 1 However, the measurement of free PHT concentration is more important because a slight fluctuation of the protein-binding ratio results in a marked change in free fraction of drug, especially seen in conditions like hypoalbuminemia caused by undernourishment, burns, and so on. 2 Hypoalbuminemia conditions that lead to decreases in availability of plasma albumin thereby increase the free PHT fraction.…”

Monitoring free plasma concentrations of phenytoin.

“…We (Peterson et al, 1982) had previously found a much wider range of free phenytoin fractions (0.097 to 0.247) in 100 epileptic patients. Rimmer et al (1984) were unable to explain this discrepancy, but suggested we may have had methodological problems. In fact, however, our methods were very similar.…”

“…Rimmer et al (1984) did not provide details of how their patient sample was selected from outpatient clinics. None of their patients had evidence of renal or hepatic dysfunction, all had normal plasma albumin levels, and only four were receiving a displacing drug (sodium valproate).…”

Therapeutic Drug Monitoring of Phenytoin Rationale and Current Status

“…In otherwise healthy epileptic palients, phenytoin is approximately 90% protein bound in serum, mostly to albumin. in patients with suspected increased free frac tion, it is more a ppropriate to moni tor the free concentration of phenytoin in serum (Baird-Lambert et al 1987: Perucca 1984: Peterson et al 1982: Rimmer et al 1984). 1987: Banh et al 1976: Perucca 1980: Rimmer et a1.…”