Abstract
Progressive reduction of plasma binding by dilution with buffer showed that uptake of sodium valproate by red blood cells was proportional to percent free drug in the supernatant. This linear relationship between the partition ratio and percent free drug suggests that the amount of sodium valproate in the red blood cells is directly related to the concentration of free drug in the suspending medium. Plasma protein binding of sodium valproate was also concentration dependent and binding was progressively reduced with increasing plasma concentration, the reduction commencing at different levels within the normal therapeutic range in different individuals. This fall in binding caused a predictable rise in red blood cell uptake of drug and the linear relationship between the RBC/P partition ratio of sodium valproate and percent free drug in plasma was maintained. Similarly, in patients with hepatic or renal impairment and consequent reduced plasma protein binding of sodium valproate, the RBC/P partition ratio was proportional to percent free drug in plasma. Uptake of free drug into red blood cells is therefore relevant in such conditions of impaired plasma protein binding. The total plasma concentration falls while the free drug concentration in plasma rises to a lesser extent than would be expected from consideration of plasma in isolation. The red blood cells therefore act as a sink to buffer the effects of the higher concentrations of free drug in plasma in states of impaired plasma protein binding.