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Individual Differences in the Disposition of Drugs Metabolised in the Body

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Abstract

Drug disposition in the body is subject to marked interindividual variability. On multiple dosing, steady state plasma concentrations obtained will be inversely proportional to the body clearance of a drug metabolised according to first order kinetics. If clearance is normally distributed, the steady state will exhibit a skew distribution. The metabolic clearance of a tricyclic antidepressant was normally distributed in 35 healthy subjects, whereas an over-representation of high clearance values was found in pooled literature data for antipyrine.

There is so far no evidence that the clearance of high clearance drugs should a priori vary more than that of low clearance drugs. If the variability in clearance is about the same, steady state plasma concentrations on multiple dosing should also have about the same dispersion. However, capacity limited elimination can be a reason for marked interindividual variability in steady state concentrations, as shown to occur, for example, with phenytoin.

If drugs are very efficiently cleared by the liver, this inevitably leads to presystemic elimination of a dose administered orally. Clearance calculated after an oral dose, estimates intrinsic hepatic clearance and is a predictor for steady state plasma concentrations of such drugs-Capacity limited elimination of alprenolol, shown as a decrease in extraction of first pass elimination with increase in dose, adds to the very pronounced variability in steady state plasma concentrations encountered for this drug.

Some further sources of interindividual differences in drug disposition — enterohepatic cycling, protein binding and distribution of drugs in the body — are discussed briefly.

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  1. Department of Clinical Pharmacology, Karolinska Institutet, Huddinge Hospital, S-141 86, Huddinge, Sweden

    Gunnar Alvan

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Alvan, G. Individual Differences in the Disposition of Drugs Metabolised in the Body. Clin Pharmacokinet 3, 155–175 (1978). https://doi.org/10.2165/00003088-197803020-00005

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