Frequency distribution of free warfarin and free phenytoin fraction values in serum of healthy human adults

Abstract

The protein binding of racemic warfarin was determined in serum from 57 normal adults (27 men and 30 women). The free fraction of warfarin (total concentration, 0.8 mug/ml) ranged from 0.0050 to 0.0186 and was log-normally distributed. The frequency distribution differs from that in rats in which the serum free fraction values of warfarin are trimodally distributed. The protein binding of phenytoin was determined in serum from 39 of the subjects. The free fraction of phenytoin (total concentration, 15 mug/ml) ranged from 0.111 to 0.155 and was unimodally distributed. There was no apparent correlation between the extent of protein binding of warfarin and phenytoin in individual serum samples. The pronounced intersubject variation in serum free fraction of warfarin observed in consistent with our previous finding that serum protein binding is an important determinant of interindividual differences in the total clearance of warfarin in man. On the other hand, the relatively narrow distribution of free phenytoin fraction values suggests that differences in serum protein binding of phenytoin are not an important cause of the prounounced interindividual differences in the total clearance of phenytoin by subjects with normal renal function.

Interaction of mixed micelles formed from glycocholic acid and lecithin with the protein binding of various drugs.

“…With both compounds the results found were similar. In absence of MM the free drug fractions corresponded to previously reported values (Guentert, 1984;Yacobi et al, 1977 all drugs bound strongly to the diazepam site on albumin. Furthermore, based on our observations with warfarin no interaction is expected with strongly bound sulphonamides (e.g.…”

Plasma concentrations of unbound phenytoin in the management of epilepsy.

“…There is disagreement in the literature concerning the magnitude of interindividual variation of phenytoin protein binding which may be explicable if the size and nature of the subject groups are considered. Some studies have reported individual differences of 5-10 fold in phenytoin unbound fraction using either equilibrium dialysis or ultrafiltration techniques (Booker & Darcey, 1973;Cronin et al, 1981); whereas other investigators have found smaller ranges (up to two-fold) in both healthy subjects and patient groups using both methodologiesequilibrium dialysis (Peterson et al, 1982;Yacobi et al, 1977) and ultrafiltration (Barth et al, 1976;Lund et al, 1972;Lunde et al, 1970;Reidenberg et al, 1971). In the present patient group the majority (43!46) had phenytoin unbound fraction in a two-fold range but for the whole group the range was five-fold.…”

Comparative pharmacokinetics of coumarin anticoagulants XLVI: Effect of treatment with phenobarbital on pharmacokinetics of (S)-(−)-warfarin in rats

“…Recent studies revealed a 15-fold range in the serum free fraction of warfarin in rats (8,12) and an approximately fourfold variation in humans (9,(13)(14)(15).…”