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Disease-induced Changes in the Plasma Binding of Basic Drugs

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Abstract

The plasma binding of basic (cationic) drugs differs from that of the more completely studied acidic drugs. Basic drugs associate with a number of plasma constituents. α1-Acid glycoprotein, lipoprotein, and albumin all appear to play an important role in the binding of most of these drugs. Acidic drugs bind largely to albumin. The variation in plasma albumin is relatively narrow and is almost always in the direction of decreased concentrations. α1-Acid glycoprotein and lipoproteins show large fluctuations due both to physiological and pathological conditions. Decreases and increases in concentration have been observed. Associated with these changes in binding proteins, both decreases and increases in plasma binding of basic drugs have been recorded. Increased binding with disease appears to be virtually unique to basic drugs.

The implications of these newly described disease-induced increases in plasma binding have yet to be explored. With the limited information in hand the following consequences are predicted. Increased binding will tend to decrease the volume of distribution of total (bound plus free) drug. The clearance will be unchanged or decreased depending upon the initial clearance of the drug and the avidity of the protein binding. As the half-life depends upon both clearance and volume of distribution, changes in it will be variable, depending upon changes in these two parameters. It is predicted that the area under the free drug plasma concentration-time curve will decrease with increasing binding after an intravenous dose while it will be unchanged after an oral dose.

The relationship of total drug plasma concentration to free drug concentration will change with changes in binding. Thus plasma concentration monitoring of drug therapy by use of total drug concentrations will be inaccurate in situations in which large variations in binding occur. Misinterpretations of both therapeutic monitoring and pharmacokinetic studies in disease slates with altered binding are likely unless these changes are appreciated.

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    K. M. Piafsky

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Piafsky, K.M. Disease-induced Changes in the Plasma Binding of Basic Drugs. Clin Pharmacokinet 5, 246–262 (1980). https://doi.org/10.2165/00003088-198005030-00004

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