Different oral phenytoin administration regimens could modify its chronic exposure and its saliva/plasma concentration ratio

ANTIEPILEPTICOS

FENITOINA

BIBLIOGRAFIA NACIONAL QUIMICA

2014

The aim of the present study was to compare plasma and saliva pharmacokinetic data obtained in healthy subjects after two different phenytoin administration regimens, having the same administration rate but different dosing interval, in order to investigate if efflux transporter induction at the blood brain barrier could be minimized, and hence a new approach for avoiding refractory epilepsy might be proposed. Six from twelve volunteers, to whom 600 mg every 72 h or 100 mg every 12 h of phenytoin were administered during 10 days, completed a two-way, two-period crossover study. Two fractions of stimulated saliva were collected simultaneously with plasma samples throughout a scheduled 24-hour period on day 10, and during the subsequent 4-day washout period.

Average plasma (P) concentrations of both the parent drug (p<0.01) and the main metabolite (p-hydroxyphenylphenytoin, p<0.05) showed higher values when 600 mg each 72 h were given. Also, the saliva first-fraction (S1) average concentration was higher (p<0.05) after 600 mg every 72 h. Conversely, S1/P average concentration ratio was higher (p<0.01) after 100 mg every 12 h. Half-lives, metabolic ratios, saliva second-fraction (S2) average concentrations, and S1/S2 ratios of average levels were not significantly different between treatments.

Results reveal that, even though the input rate was kept constant, higher doses given at long dosing intervals displayed higher systemic exposures and lower saliva/plasma exposure ratio than lower doses given at short intervals . Our hypothesis, supported by studies carried out with rats and theoretical approaches, is that efflux transporter overexpression at hepatocytes and at salivary cells would be induced by the higher local phenytoin exposures provoked by 600 mg every 72 h and by the persistent systemic exposures provoked by 100 mg every 12 h, respectively. The maintenance of systemic phenytoin concentration would be foreseen as one of the causes leading to antiepileptic treatment refractoriness, since a higher brain-to-plasma transportation of drug could be induced.

Maybe once-daily dosing of phenytoin would be preferable to twice or three times a day administration regimens. Despite the fact that avoiding peak-trough oscillation was always the aim of pharmacotherapy, it might be more appropriate for patients under phenytoin treatments to increase both dose and dosing interval in order not to contribute to the installation of pharmacoresistance.

Journal of Medical and Pharmaceutical Innovation v. 1, no. 6S, 2014.-- p. 35-43

HE BAI (Kelvin)

2014

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Inglés

Artículo

ISSN: 2347 - 8136

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