The 'apparent clearance' of free phenytoin in elderly vs. younger adults

The clearance of many drugs is reduced in the elderly, but the data regarding phenytoin are conflicting. Most studies have estimated phenytoin metabolic clearance using total drug concentrations (bound plus unbound), which may be confounded by protein binding effects. Free phenytoin concentrations are independent of protein binding and should more accurately reflect true metabolic clearance changes in elderly patients.

The two studies reported in this paper suggest a trend towards reduced free phenytoin 'apparent clearance' in the elderly, although statistically significant results were not found. Other published studies have largely found similar trends, suggesting an age effect.

To test the hypothesis that the 'apparent clearance' of free phenytoin is reduced in elderly patients.

Two separate studies were conducted comparing free phenytoin 'apparent clearance' in elderly vs. younger adults. The first study was a retrospective analysis of free phenytoin concentrations measured at Christchurch Hospital from 1997 to 2006. In the second study free phenytoin concentrations were measured prospectively in ambulatory subjects who were taking phenytoin regularly.

In the retrospective study (n= 29), free phenytoin 'apparent clearance' was 0.27 +/- 0.04 l kg(-1) day(-1) (95% CI 0.19, 0.34) in the elderly cohort vs. 0.37 +/- 0.06 l kg(-1) day(-1) (95% CI 0.22, 0.52) in younger adults, but the difference was not statistically significant. In the prospective study, free phenytoin 'apparent clearance' showed a non-significant trend to being reduced in the elderly patients (0.12 +/- 0.02 l kg(-1) day(-1), 95% CI 0.07, 0.17) compared with the younger cohort (0.18 +/- 0.07 l kg(-1) day(-1), 95% CI 0.09, 0.26) in those not taking interacting drugs (n= 21).

This research does not prove the hypothesis that the 'apparent clearance' of free phenytoin is reduced in the elderly. However, the trends found in these two studies are supported by trends in the same direction in other published studies, suggesting an age effect.