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The effect of rifampin on isoniazid-induced hepatotoxicity in rabbits Petricca, Giorgio Maximillian


The objective of this study was to examine the effect of rifampin pretreatment on isoniazid-induced hepatotoxicity. For more than 25 years, it has been suggested that the concomitant administration of rifampin with isoniazid potentiates the hepatotoxicity induced by isoniazid. However, evidence to support this suggestion has been non-conclusive. Isoniazid and rifampin are still the two most commonly used drugs in the prophylaxis and treatment of tuberculosis. The relatively high incidence of tuberculosis throughout the world has not diminished and with more than 30 million deaths in this decade, tuberculosis is still the major killer among all single pathogens. Isoniazid is associated with potentially fatal liver damage in 1 - 2% of individuals exposed. However, the mechanism of isoniazid-induced hepatotoxicity remains largely unknown at the present time. Our laboratory has recently established a reliable model of isoniazid-induced hepatotoxicity in rabbits with features similar to those seen in humans. The dosing regimen in this study consisted of seven days rifampin pretreatment (50 mg/kg/day) followed by concomitant rifampin and isoniazid (each day consisting of an initial dose of 50 mg/kg followed by 3 x 35 mg/kg doses) administration for two days. Controls for each of these drugs were also included in the study design. The aim of the present study was to determine the effect of rifampin on the degree of isoniazid-induced hepatotoxicity, as well as to increase our understanding of the mechanism of isoniazid-induced hepatotoxicity. The following are the major findings in this thesis. Using the aforementioned protocol, rifampin significantly protected rabbits from isoniazid-induced hepatic necrosis. However, rifampin had no significant effect on plasma levels of hydrazine at 12 or 32 hours of isoniazid dosing in rabbits receiving rifampin plus isoniazid. Rifampin treatment alone significantly decreased cytochrome P-450 (CYP) 2E1 and significantly increased cytochrome P-450 reductase activities. The protective effect of rifampin in INH-induced hepatotoxicity could be due to its effect on CYP2E1 or reductase activities or another effect of rifampin not measured in this study. In conclusion, the protective effect of rifampin on isoniazid-induced hepatic necrosis observed in this study is concordant with the results of a double-blind placebo-controlled trial in humans, adding to the support for the usefulness of this rabbit model.

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