Bioavailability of Phenytoin Sodium Capsules Available in Thailand Part II : In vivo Study
CHUTHAMANEE SUTHISISANG, Ph.D.*, NALIN PAYAKACHAT, M.Sc.**, SUVA TNA CHULA VA TNA TOL, Ph.D.***, SOMCHAI TOW AN ABUT, M.D.****
Affiliation : * Department of Pharmacology, Faculty of Pharmacy, Mahidol University, Bangkok 10400, ** Department of Pharmacology, Faculty of Pharmaceutical Science, Silapakom University, Nakompathom 73000, *** Department of Pharmacy, Faculty of Pharmacy, Mahidol University, Bangkok 10400, **** Prasat Neurological Institute, Bangkok 10400, Thailand.
Abstract
Four phenytoin brands, dilantin® and three local brands (brand A, B and C) were selected
for the bioavailability study. The study was carried out in 16 healthy male Thai volunteers with the
average age of 21 years old. A single oral dose of 300 mg (three capsules of 100-mg) phenytoin
sodium was given to subjects following an 8 hour-overnight fast. The tested drugs were given in a
single-blind randomized crossover with at least 2 weeks of washout period. Venous blood samples
of approximately 5 ml were drawn before medication and at 1, 2, 4, 6, 8, 10, 12, 24, 48 and 72 hours
post dosing. Plasma phenytoin concentrations were determined by HPLC assay.
The pharmacokinetic parameters were calculated from the plasma-concentration time
curve of an innovator brand, dilantin® , by PCNONLIN program. Elimination rate constant and
half-life were 0.2 h-1 and 19 h, respectively. The maximum concentration (Cmax) and time to
peak (Tmax) were 1.98 !Jg/ml and 9.6 h, respectively. Bioavailability study was determined by
comparing the area under the plasma concentration time curve (AUC), maximum plasma concen-
tration (Cmax) and time to reach maximum plasma concentration (Tmax) by using ANOV A. The
result indicated that two local brands (brand A and brand C) were not bioequivalent to the inno-
vator in terms of Cmax and AUCo-w whereas Tmax was not significantly different among these 4
brands. Cmax and AUC of brand A and C were significantly higher than the innovator brand. In
addition, the plasma concentration time profile of brand C was also different from other brands
with the steep peak which yielded a Cmax value double that of the Cmax of the innovator. However,
brand B (from Research and Development Institute, Government Pharmaceutical Organization)
was bioequivalent to dilantin® after 4 times of product formulation adjustment.
This present study demonstrated that the local products (brand A and brand C) were not
bioequivalent with the innovator. Thus, the interchange from one brand to another must be
performed cautiously or should be avoided, otherwise phenytoin blood levels should be monitored
closely together with the clinical signs and symptoms of the patients.
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