Relationship between protein binding and extravascular drug concentrations of a water-soluble drug, cytosine arabinoside.

The degree of binding of a drug to plasma proteins has a marked effect on its distribution, elimination, and pharmacological effect. Since only the unbound fraction is available for distribution into extravascular space, the ratio of drug in cerebrospinal fluid (CSF) or saliva to that in plasma is often regarded as a physiological measure of the free fraction of a drug. CSF: plasma and saliva: plasma ratios of cytosine arabinoside (araC) have been measured in patients with acute leukaemia and found to be 0.1-0.28, implying a binding of 72-90%. The protein binding of araC was measured by equilibrium dialysis in the plasma of patients with acute leukaemia at presentation. The mean binding ratio was 2.3 +/- 6.8, implying that there was little or no protein binding. There was no correlation between alpha-1 acid glycoprotein (AAG) levels and protein binding. The low CSF and saliva: plasma araC ratios found, suggest that drugs such as araC which have low lipid solubility do not pass freely into extravascular space. Thus the CSF or saliva: plasma ratio cannot be considered a good physiological measure of protein binding for drugs with poor lipid solubility.