Validity of carbon tetrachloride-induced liver damage and nephrectomy as biological procedures for determining fate and excretion of anticonvulsant drugs.

Carbon tetrachloride-induced liver damage and nephrectomy are commonly used to determine the fate and excretion of anticonvulsant drugs. It is generally assumed that such alterations do not otherwise affect the response of the central nervous system to such drugs or to the tests employed to measure their activity. In order to test this assumption, the effects of carbon tetrachloride-induced liver damage and of nephrectomy on the pattern of maximal electroshock seizures (MES) and on the anticonvulsant activity of drugs with known metabolic fates were determined. The effective dose fifty (ED50) of barbital sodium (excreted by the kidney) and of pentobarbital sodium (detoxified by the liver) was determined in rats at various time intervals after drug administration by the MES test (150 mA, 0.2 sec., a.c., corneal electrodes). The effects of carbon tetrachloride on MES pattern and on the anticonvulsant activity of the two drugs tested were determined U8 hours after the subcutaneous injection of carbon tetrachloride (2 ml./kgm. of a 50 per cent w/v solution in peanut oil). The effects of partial hepatectomy and bilateral nephrectomy on MES pattern and on the anticonvulsant activity of the two barbiturates were determined 12 hours after the surgical procedures were performed. The effects of administration of carbon tetrachloride on glomerular filtration rate (measured by inulin clearance) and on the excretion of barbital sodium were also studied. The results were analyzed for statistical significance and may be summarized as follows: 1. Carbon tetrachloride-induced liver damage had no significant effect either on the MES pattern or on the ED50s of barbital sodium, but significantly decreased the ED50s of pentobarbital sodium at all time intervals studied. 2. Partial hepatectomy altered slightly the MES pattern, but had no significant effect on the ED50s of barbital sodium. In contrast, the ED50s of pentobarbital sodium were (significantly decreased at all time intervals studied. 3. Bilateral nephrectomy had no significant effect either on the MES pattern or on the ED50s of pentobarbital sodium, but significantly decreased the ED$0 of barbital sodium by the 12-hour interval. 4. Carbon tetrachloride administration did not significantly alter glomerular filtration rate, as measured by inulin clearance. On the other hand, barbital sodium excretion was a significantly prolonged in treated animals. It is concluded that carbon tetrachloride-induced liver damage and nephrectomy provide useful methods for the study of the fate and excretion of anticonvulsant drags in rats.