Summary
A simple pharmacokinetic model, incorporating linear plasma protein binding, linear tissue binding, and first order elimination of free (unbound) drug, was studied. If Clp is the plasma clearance, Vf is the “true” volume of distribution of free drug, β is the apparent elimination rate constant, σ is the fraction of the drug which is free in plasma, f is the fraction of the drug which is free in the entire body, kf is the intrinsic elimination rate constant for free drug, and A oTB is the initial amount of drug which is bound to tissues, then the model indicates that the following relationships hold: (1) Clp = Vfσ kf; (2) β = f kf; and Vdext = (σ/f) Vf. Only σ, and not f, can be measuredexperimentally. Dividing Clp by σ provides an estimate of the intrinsic clearance of free drug, Vfkf. A plot of Vdext versus σ has an intercept equal to Vf, and the ratio of the slope/intercept is an estimate of A oTB /A of , where A of is the initial amount of free drug (equal to Vf times initial concentration of free drug in plasma). Thus, an estimate of A oTB may be obtained. Dividing the intrinsic clearance by Vf provides an estimate of kf. Thus, theoretically, estimates of Vf, kf, A oTB and f may be obtained. The variables are not separated when β is plottedversus σ, and curvature of such plots is expected; no useful information is obtained from such plots.
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Partly supported by Public Health Service Grant 5-P-11-GM 1559 and partly by Grant 1RO1AAOO683-O1A1 from the National Institute on Alcohol Abuse and Alcoholism, Rockville, Maryland.
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Wagner, J.G. Simple model to explain effects of plasma protein binding and tissue binding on calculated volumes of distribution, apparent elimination rate constants and clearances. Eur J Clin Pharmacol 10, 425–432 (1976). https://doi.org/10.1007/BF00563079
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DOI: https://doi.org/10.1007/BF00563079