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Interaction of griseofulvin with metoclopramide, propantheline and phenobarbital in the rat Jamali, Fakhredin

Abstract

Phenobarbital pretreatment, in man and rat, has been observed to decrease the plasma levels attained after administration of solid dosage forms of griseofulvin. Various mechanisms including induced metabolism, increased gastrointestinal motility, diminished dissolution rate or a complex mechanism involving enzyme induction, first-pass metabolism and distribution rate-limited elimination of griseofulvin have been suggested. This present investigation was initiated in an attempt to clarify the mechanism of this interaction. Intravenous administration of griseofulvin in control and phenobarbital dosed rats confirmed that no obvious differences existed in griseofulvin metabolism under the experimental conditions. The influence of gut motility on the absorption of griseofulvin administered as single oral doses of either 100 mg/kg in 0.5% Tween 80 (suspension) or 50 mg/kg in 100% polyethylene glycol (PEG) 600 (solution) was evaluated by pretreating rats with single intraperitoneal doses of either 10 mg/kg metoclopramide hydrochloride or 5 mg/kg propantheline bromide two hours prior to griseofulvin administration. Metoclopramide pretreatment accelerated the absorption rate of griseofulvin suspension (the time of peak-plasma level, Tmax was shortened from 6 to 3 hours) but reduced its total absorption by 50%. Conversely, this treatment regimen increased the total absorption of griseofulvin by 230% when administered in solution form. Propantheline preadministration, however, retarded the absorption rate (Tmax prolonged from 6 to 19 hours) but increased the total absorption of a suspension of griseofulvin by 50% The propantheline treatment regimen elicited a sharply contrasting effect by decreasing the total absorption (23%) of griseofulvin when given in solution form. It was therefore, concluded that a) the interaction of griseofulvin with metoclopramide and propantheline is formulation-dependent and b) the gut motility has a significant influence on the absorption of griseofulvin. The interaction between griseofulvin and phenobarbital was evaluated by administering single oral doses of a) suspension of 100 mg/kg griseofulvin in either 0.5% or 2% Tween 80, b) suspensions of 20 or 100 mg/kg griseofulvin in 70% PEG 300, or c) solutions of 50 mg/kg griseofulvin in 100% PEG 600. Test rats received single oral doses of 15 mg/kg sodium phenobarbital 24 hours prior to griseofulvin administration. The treatment reduced the total absorption of griseofulvin administered in 0.5% Tween 80 by 50%. The extent of the interaction was reduced to an insignificant level on increasing the concentration of Tween 80 from 0.5% to 2%. Phenobarbital did not alter the apparent rate of griseofulvin absorption since the peak plasma concentrations were coincident between control and test animals. Phenobarbital treatment did not affect the availability of griseofulvin when administered as suspensions or solutions in PEG as reflected by equivalent areas under the plasma curves at the same dose level in test and control animals. It can therefore be concluded that the interaction between griseofulvin and phenobarbital in the rat is a) a formulation-dependent phenomenon and b) not caused by either enzyme induction or an increased gut motility. It is concluded that when griseofulvin is administered as a suspension in 0.5% Tween 80 the phenobarbital-griseofulvin interaction in the rat is caused by a complex mechanism resulting in a diminished dissolution rate and subsequent decreased absorption.

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