Plasma Protein Binding of Acidic Drugs

TABLE 5.3 Effect of Impaired Renal Function on Phenytoin Kinetics 

FIGURE 5.2 Comparison of free and total plasma phenytoin levels in a patient with normal renal function and in a functionally anephric patient both are treated with a 300-mg daily phenytoin dose and have identical Although free phenytoin levels are 

g/mL in both patients, phenytoin is only 84% bound (16% free) in the functionally anephric patient, compared to 92% bound (8% free) in the patient with normal renal function. For that reason, total phenytoin levels in the functionally anephric patient are only 5 p,g/mL, whereas they are 10 jxg/mL in the patient with normal renal function. 

Plasma Protein Binding of Basic and Neutral Drugs 

The protein binding of basic drugs tends to be normal or only slightly reduced (25). In some cases, this may reflect the facts that these drugs bind to oti-acid glycoprotein and that concentrations of this glycoprotein are higher in hemodialysis-dependent patients than in patients with normal renal function. 

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Generally, plasma protein binding of acidic drugs (e.g., warfarin, pheny-toin) is decreased in CKD, whereas binding of basic drugs (e.g., quinidine, lidocaine) is usually normal or slightly decreased or increased. 

Distribution - Valproic acid is rapidly distributed. Volume of distribution of total or free valproic acid is 11 or 92 L/1.73 m, respectively. Valproic acid has been detected in CSF (approximately 10% of total concentrations) and milk (about 1% to 10% of serum concentrations). Therapeutic range is commonly considered to be 50 to 100 mcg/mL of total valproate. The plasma protein binding of valproate is concentration-dependent. Protein binding of valproate is reduced in the elderly, in patients with chronic hepatic diseases, in patients with renal impairment, and in the presence of other drugs (eg, aspirin). Conversely, valproate may displace certain protein-bound drugs (eg, phenytoin, carbamazepine, warfarin, tolbutamide). 

Some disease states (e.g., hyperalbuminemia, hy-poalbuminemia, uremia, hyperbilirubinemia) have been associated with changes in plasma protein binding of drugs. For example, in uremic patients the plasma protein binding of certain acidic drugs (e.g., penicillin, sulfonamides, salicylates, and barbiturates) is reduced. 

Since milk is more acidic (pH 6.5) than plasma, basic compounds (e.g., alkaloids, such as morphine and codeine) may be somewhat more concentrated in this fluid. In contrast, the levels of weak organic acids will probably be lower than those in plasma. In general, a high maternal plasma protein binding of drug will be associ-... 

The overall accuracy of the predictions, assessed as the mean-fold error of prediction of the test set was 2.03, making this approach one that would possess suitable accuracy for use in drug design and human pharmacokinetic predictions. Similar methods developed separately for acids and bases showed an improvement in accuracy. This investigation also included a prediction of unbound VD, which should represent a simpler parameter to predict since it would be based only on tissue binding and not plasma protein binding. However, it is interesting to note that this approach was less accurate for this parameter, which would be unexpected. 

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