The purpose of this investigation was to determine if administration of heparin causes displacement of an acidic drug from serum protein binding sites in vivo as has been suggested by several groups of investigators. Rats were injected and infused with phenytoin to produce steady-state serum concentrations of about 25 micrograms/ml. After 2 hr, some of the animals also received injections and infusions of either heparin or salicylic acid. Salicylic acid (about 300 micrograms/ml), a classical inhibitor of phenytoin protein binding, reduced the steady-state serum concentration of total (free plus bound) phenytoin but had no significant effect on the steady-state serum concentration of free phenytoin or on the concentrations of phenytoin in cerebrospinal fluid and brain. The concentrations of phenytoin in cerebrospinal fluid were almost identical to the free phenytoin concentrations in serum. Similar effects were observed with respect to 5-(p-hydroxyphenyl)-5-phenylhydantoin and were found to be due to displacement of this major metabolite of phenytoin from serum protein binding sites by salicylate. Heparin administration caused an apparent increase of the steady-state plasma concentration of free phenytoin when determined as the product of the concentration of total phenytoin and the free fraction measured by in vitro equilibrium dialysis. Since heparin treatment had no significant effect on the total concentrations of phenytoin in plasma, cerebrospinal fluid and brain, it is concluded that the apparent displacement of phenytoin from plasma proteins occurs in vitro, after collection of blood samples from heparinized animals.
The effect of the non-steroidal anti-inflammatory agent naproxen on the protein binding of racemic warfarin in pooled human serum was determined by equilibrium dialysis. The free fraction of warfarin in serum increased practically linearly with increasing naproxen concentration. At the highest naproxen concentration tested (400 mcg/ml), the warfarin free fraction was 74% larger than the control free fraction value.
Cardiac amyloidosis is expressed as a restrictive myocardiopathy. Echocardiography suggests the diagnosis. There is a great difference between the prognosis of senile cardiac amyloidosis and "AL" amyloidosis. We illustrate this point with two case reports.
