Selectivity of cholestyramine treatment on hepatic mixed function oxidase activity

The possibility that oral cholestyramine treatment might indirectly increase hepatic drug oxidations was investigated in rats using pentobarbital, antipyrine, zoxazolamine, and aminopyrine as probes of the hepatic mixed function oxidase system and in humans using amobarbital and antipyrine as probes. Cholestyramine pretreatment of rats for 5 days (87.5 mg/kg twice daily by stomach tube) shortened pentobarbital sleep times, decreased antipyrine-induced hypothermia, but did not influence either zoxazolamine paralysis times or the in vitro N-demethylation of aminopyrine. Neither pentobarbital nor antipyrine pharmacokinetics in rats were affected by the cholestyramine pretreatment. Similarly, in two-way crossover studies with human subjects, a 5-day oral cholestyramine pretreatment (4 g 3 times daily) had no demonstrable effect on the pharmacokinetics of single doses of amobarbital (200 mg i.v.) or antipyrine (500 mg per os). After cholestyramine pretreatment, a trend toward diminished CNS depression produced by amobarbital was observed, but the effect was not statistically significant. The results suggest that hepatic mixed function oxidases in rats for which aminopyrine, antipyrine, pentobarbital, and zoxazolamine are substrates and that hepatic mixed function oxidases in humans for which amobarbital and antipyrine are substrates are not significantly affected by cholestyramine pretreatment.