Phenotypic interaction of simultaneously administered isoniazid and phenytoin in patients with tuberculous meningitis or tuberculoma having seizures

Treatment of tuberculous meningitis or tuberculoma has become complicated because of adverse drug interactions found amongst antitubercular and anticonvulsant drugs. The aim of the study is to evaluate the effect of simultaneously administered isoniazid (300 mg/day) and phenytoin (300 mg/day) on 60 patients with tuberculous meningitis or tuberculoma having seizures. Plasma samples were analyzed for isoniazid, acetylated-isoniazid (AcINH) and phenytoin levels by high performance liquid chromatography at 3 h of drugs administration and patients were classified as rapid or slow acetylator on the basis of metabolic ratio of isoniazid (Rm) and percentage of acetylated-isoniazid (%AcINH). Out of 60 patients studied, 23 were slow acetylators and 37 were rapid acetylators. Slow acetylators revealed higher plasma isoniazid levels and lower plasma AcINH levels, metabolic ratio and %AcINH as compared to rapid acetylators. Plasma phenytoin levels were found to be significantly higher (above therapeutic range) in slow acetylators as compared to rapid acetylators. Plasma phenytoin concentration was moderately strong, negatively correlated with metabolic ratio (r=−0.439, P<0.001) and %AcINH (r=−0.729, P<0.001). Eight comatose patients (34.8%) also showed significantly higher plasma phenytoin levels. Our results suggest that assessment of acetylator status and plasma phenytoin level is critical for dose optimization of isoniazid and phenytoin and to predict the patients at risk of intoxication.