Phenobarbital-valproic acid interaction

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Abstract
The effect of subchronic valproate [VP] treatment on the single-dose kinetics of phenobarbital [PB] was investigated in 6 normal human subjects. The study consisted of 2 drug treatments assigned through randomized crossover design. In one treatment subjects received a 60-mg dose of PB orally. In the other, subjects received 250 mg VP orally 2.times./day for 14 consecutive days and a 60-mg dose of PB orally on day 4. Over 12 days 19 plasma samples and 2 48-h urine samples were collected during each treatment. Plasma and urine PB levels were determined by GLC interfaced with mass spectrometer in a chemical ionization mode and plasma VP acid levels by GLC. VP induced several changes in the elimination parameters of PB: PB half-life rose from 96 to 142 h; plasma clearance fell from 4.2 to 3.0 ml/h per kg; renal clearance was unchanged, and metabolic clearance fell from 3.3 to 2.0; renal clearance was unchanged, and metabolic clearance fell from 3.3 to 2.0 mg/h per kg; the fraction of dose excreted unchanged rose from 0.22 to 0.33, and the fraction of dose metabolized fell from 0.78 to 0.67. VP apparently inhibits PB metabolism. Valproate and phenobarbital are both used as anti-epileptic agents.