Efflux in isolated hepatocytes as a possible correlate of secretion in vivo: induced exit of the folic acid analog methotrexate, by dibutyryl cyclic AMP or isobutyl methyl xanthine

Dibutyryl cyclic AMP and isobutyl methyl xanthine induce release of freely exchangeable methotrexate as well as a small component of apparently bound drug from freshly isolated rat hepatocytes; methotrexate polyglutamate derivatives are retained. These observations, as well as the energy dependence of methotrexate efflux induced by dibutyryl cyclic AMP suggests that this may represent the induction of a "secretory" phenomenon in which drug is released into the capillary sinusoid and/or the bile canaliculus when the hepatocyte is in its normal spatial orientation in the liver lobule in vivo. Because there is evidence that this folic acid analog and bile salts utilize the same transport mechanism in these cells, this phenomenon may have general physiological as well as pharmacologic relevance and the isolated hepatocyte may be a useful model system to study mechanisms of hepatic secretion at the cellular level.