Single dose phenytoin clearance during erythromycin treatment

Abstract

The effects of erythromycin on the single dose kinetics of phenytoin (PHT) were studied in eight healthy, male volunteers in a crossover study. PHT was administered in a single, oral 300 mg dose either alone or after 5 days of a 7 day erythromycin regimen. Erythromycin base (333 mg) was taken orally every 8 hr. PHT concentrations were measured in plasma collected at 0, 2, 4, 8, 12, 24, 36, and 48 hr after PHT administration and in saliva at 48 hr. PHT was assayed by a polarized immunofluorescent technique. Mean (+/- SD) control values for PHT intrinsic clearance, CLint/F; volume of distribution, V/F; and half-life, t 1/2 were 0.028 (+/- 0.009) 1 X hr-1 X kg-1, 0.97, (+/- 0.33) l/kg, and 27.3 (+/- 12.4) hr, respectively. During erythromycin treatment CLint/F was 0.026 (+/- 0.011) 1 X hr-1 X kg-1, V/F was 0.87 (+/- 0.23) l/kg, and t 1/2 was 31.2 (+/- 26.1) hr. None of the mean values changed significantly due to erythromycin treatment (p greater than 0.05). Estimates of intrinsic unbound PHT clearance, CL'int/F, based upon the 48 hr salivary PHT values were 0.403 (+/- 0.170) 1 X hr-1 X kg-1 and 0.352 (+/- 0.152) 1 X hr-1 X kg-1 for the control and erythromycin phases, respectively (p greater than 0.05). When intrinsic unbound PHT clearance, CL'int/F, was calculated from CLint/F using a mean free PHT fraction, fu, of 0.069 a good correlation between CL'int/F and CL'int/F could be shown. Evaluation of the interaction on the basis of multiple plasma sample data and single salivary sample data led to the same conclusion. Even though erythromycin failed to significantly decrease mean PHT clearance, occasionally large changes in PHT clearance accompanying erythromycin treatment provide sufficient incentive to closely monitor patients taking both drugs.