The unbound fraction of several acidic drugs may be increased in uremia, even when the concentration of the serum albumin is normal. The reduction in binding of phenytoin is related to the decrease in renal function ( 20% unbound drug at a serum creatinine level of 10-12 mg/dl compared to about 10% unbound with normal renal function). One practical implication of this information is that the uremic patient whose total plasma phenytoin level is below the therapeutic range may still have adequate seizure control because the unbound concentration is in the middle or high usual therapeutic range. If necessary, total and unbound plasma concentrations should be measured.

In contrast to acidic drugs, the protein binding of basic drugs seems to be normal in uremic patients, with triamterene being the one known exception. Little is known about neutral drugs, but available information shows that the unbound fraction of digitoxin is increased in uremia.

It has been shown for some highly bound drugs, such as phenytoin and clofibrate, that in patients with nephrotic syndrome and essentially normal creatinine clearance the decreased serum albumin is associated with a proportional increase in the fraction of unbound drug. However, because an increase in clearance the total levels decrease and unbound concentration does not change significantly.

Little is known about alteration in volume of distribution in renal diseases, but it has recently been shown that the volume of distribution for phenytoin is increased in nephrotic patients.