Binding and distribution of restrictively and non-restrictively eliminated drugs to serum and liver cell cytosol: effects of volatile anaesthetics.

The in vitro binding and distribution of drugs to human serum and rat liver cytosol was examined in a three-compartment distribution dialysis system where the free drug concentration could be determined. The effects of high concentrations of volatile anaesthetics and their metabolites on distribution and binding were also investigated. Restrictively eliminated drugs (warfarin, phenytoin, diazepam) distributed more slowly and demonstrated lower cytosol:serum binding ratios (0.09, 0.11 and 0.11, respectively) as compared with the non-restrictively eliminated drugs propranolol and prazosin with distribution ratios of 0.62 and 1.1, respectively. The rapid distribution in favour of liver cytosol may partly explain the high hepatic extraction ratio of non-restrictively eliminated drugs in vivo. Enflurane showed the most significant influence on drug binding as it was the only compound to displace propranolol and prazosin from serum. Furthermore, enflurane displaced phenytoin and diazepam from both serum and cytosol simultaneously, creating marked increases in the free drug concentrations of 60 and 113%, respectively. Halothane was shown to be a weaker agent than enflurane with respect to the ability to displace drugs from serum proteins and liver cytosol. Neither enflurane nor halothane influenced significantly the binding or distribution of warfarin. In contrast, trifluoroacetic acid did not displace any drugs from cytosol, but displaced restrictively eliminated drugs from serum. It is suggested that the ability of enflurane to displace specific drugs from both serum proteins and liver cytosol may be of clinical relevance.