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How does obesity affect residence time dispersion and the shape of drug disposition curves? Thiopental as an example

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Abstract

The effect of obesity on the shape of drug disposition curves was explained using the residence time concept without assuming well-mixed compartments. The mean (MDRT) and relative dispersion \({({\rm RD}_{\rm D}^2)}\) of disposition residence time of drug were predicted as function of percentage body fat by lumping the organs into fat and nonfat tissues, utilizing the fact that MDRT and \({{\rm RD}_{\rm D}^2}\) act as a scale and shape parameter of disposition curves, respectively. The longer sojourn time of lipophilic drugs in adipose tissue leads to an increase in \({{\rm RD}_{\rm D}^2}\) when the fraction of body fat increases. This explains the change in the shape of disposition curves observed in obese patients, where the increase in MDRT is accompanied by a proportionately great prolongation of the terminal half life. The model also predicts a decrease in whole body distribution clearance with increasing residence time dispersion \({({\rm RD}_{\rm D}^2)}\) .

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Abbreviations

\({C_{\rm D}(t)}\) :

Drug disposition curve after i.v. bolus injection

MDRT:

Mean disposition residence time

VDRT:

Variance of disposition residence time

\({{\rm RD}_{\rm D}^2}\) :

Relative dispersion of disposition residence time

\({{\rm RD}_{\rm C}^2}\) :

Relative dispersion of circulatory transit time

\({{\rm RD}_{\rm B}^2}\) :

Relative dispersion of vascular transit time

CL:

Total elimination clearance

\({{\widetilde{\rm CL}}}\) :

CL/(Body weight) = CL/V body

CLM :

Whole body distribution clearance

Q :

Cardiac output

i = F:

Fat tissue

i = NF:

Nonfat tissue

Q i :

Blood flow to tissue i

qF:

\({Q_{\rm F}/Q}\)

E :

Total extraction ratio (= CL/Q)

\({K_{{\rm p},i}}\) :

Tissue:plasma partition coefficient of tissue i

\({k_{\rm F}}\) :

\({K_{{\rm p,F}}/K_{{\rm p,NF}}}\)

V i :

Physiological volume of tissue i

bf:

\({V_{\rm F}/V_{\rm body}}\)

V ss :

Volume of distribution at steady-state

\({\tilde{V}_{\rm ss}}\) :

\({V_{\rm ss}/V_{\rm body}}\)

V z :

Terminal distribution volume

t 1/2,z :

Terminal half-live

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  1. Section of Pharmacokinetics, Department of Pharmacology, Martin Luther University, Halle-Wittenberg, 06097, Halle, Germany

    Michael Weiss

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Weiss, M. How does obesity affect residence time dispersion and the shape of drug disposition curves? Thiopental as an example. J Pharmacokinet Pharmacodyn 35, 325–336 (2008). https://doi.org/10.1007/s10928-008-9090-8

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  • DOI: https://doi.org/10.1007/s10928-008-9090-8

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