Effect of doses on the bioavailability of phenytoin from a prompt-release and an extended-release preparation: single dose study.
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.


METHODS
Eight healthy male volunteers were given single oral doses of 100, 200, and 300 mg of a prompt-release preparation (Ditoin) and an extended-release phenytoin (Dilantin Kapseals) preparation 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 pharmacokinetic parameters were analyzed by non-compartmental model.


RESULTS
Rate of phenytoin absorption from the prompt-release preparation was more prolonged after the 300mg dose (T(max) 4.5 h) than those of the 100- and 200-mg doses (T(max) 3.5 and 3 h, respectively). Similarly, the T(max) 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 C(max) of all doses of the prompt-release preparation were higher than those values of the extended-release preparation with the mean C(max) 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 absorption (AUC(0-infinity)) of 100-mg phenytoin was bioequivalent between the two preparations [mean AUC ratio (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).


CONCLUSIONS
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.
Rojanasthien
Noppamas
N
Department of Pharmacology, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand. nrojanas@mail.med.cmu.ac.th
Chaichana
Nuchanart
N
Teekachunhatean
Supanimit
S
Kumsorn
Boonyium
B
Sangdee
Chaichan
C
Chankrachang
Siwaporn
S
D000328:Adult; D019540:Area Under Curve; D001682:Biological Availability; D002851:Chromatography, High Pressure Liquid; D018592:Cross-Over Studies; D003692:Delayed-Action Preparations; D016903:Drug Monitoring; D006801:Humans; D008297:Male; D010672:Phenytoin / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D013997:Time Factors
D003692:Delayed-Action Preparations; D010672:Phenytoin