Intrahepatic disposition of xenobiotics in relation with their partition coefficient.

To investigate the influence of the partition coefficient of a drug upon its intracellular disposition, ouabain, chloramphenicol and tetracycline kinetics were studied in the rat liver. Under ether anesthesia, various doses of the test drugs were injected into the portal vein, and the rats sacrificed at varying times later. The liver was homogenized and the drugs measured in the homogenate, and in the subcellular fractions. Intracellular distribution was almost instantaneous. Ouabain (P, l-octanol/H2O = o.01), tetracycline (P,l-octanol/h2) = 0.03) and chloramphenicol metabolites accumulated preferentially in the cytosol fraction, and chloramphenicol (P, l-octanol/H2O = 13.8) in the smooth microsomal fraction. There was an excellent correlation between the percentages of the test drugs recovered in the microsomal fractions relative to the homogenates and the log P of these substrates. None of the drugs nor their metabolites accumulated in the Golgi fraction. The hepatic uptake of ouabain was similar to that observed with chloramphenicol. However the hepatic uptake of tetracycline was approximately 50% regardless of the dose tested. Ouabain, chloramphenicol and tetracycline were eliminated in a first order fashion. However, the transport mechanisms of elimination of chloramphenicol glucuronide were saturated. It is concluded that the intrahepatic distribution is a passive process which depends on the partition coefficient of the test drugs.