Effect of Doses on the Bioavailability of Phenytoin from a Prompt-Release and an Extended-Release Preparation: Single Dose Study
Noppamas Rojanasthien MD*, Nuchanart Chaichana PhD*, Supanimit Teekachunhatean MD*, Boonyium Kumsorn MS*, Chaichan Sangdee PhD*, Siwaporn Chankrachang MD**
Affiliation : * Department of Pharmacology, Faculty of Medicine, Chiang Mai University, Chiang Mai ** Department of Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai
Objective : To determine the effect of doses on the bioavailability of a prompt-release and an extended-release
phenytoin capsule after given as single doses.
Materials and Methods : Eight healthy male volunteers were given single oral doses of 100, 200, and 300 mg of
a prompt-release preparation (Ditoin(cid:31)) and an extended-release phenytoin (Dilantin Kapseals(cid:31)) prepara-
tion in a crossover design with a two weeks washout period after an overnight fast. Serial blood samples were
collected over 72 h post-dose. Plasma phenytoin concentrations were determined by HPLC and pharmacoki-
netic parameters were analyzed by non-compartmental model.
Results : Rate of phenytoin absorption from the prompt-release preparation was more prolonged after the 300-
mg dose (Tmax 4.5 h) than those of the 100- and 200-mg doses (Tmax 3.5 and 3 h, respectively). Similarly, the Tmax
of the 200- and the 300-mg extended-release preparation (5.5 and 4 h) were more prolonged than the 100-mg
dose (3 h). Bioequivalence analysis showed that the Cmax of all doses of the prompt-release preparation were
higher than those values of the extended-release preparation with the mean Cmax ratio (90% CI) of 1.32 (1.24-
1.40), 1.26 (1.14-1.40), and 1.29 (1.10-1.51) for the 100-, 200- and 300-mg doses, respectively. The extent of
) of 100-mg phenytoin was bioequivalent between the two preparations [mean AUC ratio
absorption (AUC0-∞
(90% CI) of 1.15 (1.11-1.18)], however, for higher doses, the prompt-release products produced higher
bioavailability than the extended-release products [mean AUC ratio (90% CI) of 1.19 (1.07-1.33) and 1.17
(0.98-1.38), respectively for the 200- and 300-mg doses]. The difference in the bioavailability did not affect
the elimination of phenytoin and their half-lives were comparable (11-13 h).
Conclusion : The bioavailability of phenytoin from both preparations increased proportionally over the dose
range of 100-300 mg, however, the bioavailability of the prompt-release preparation was higher than the
corresponding doses of the extended-release product.
Keywords : Phenytoin, Bioavailability, Single-dose
