Journal of Pharmacokinetics and Pharmacodynamics

, Volume 35, Issue 3, pp 325–336

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

Authors

    • Section of Pharmacokinetics, Department of PharmacologyMartin Luther University, Halle-Wittenberg
Article

DOI: 10.1007/s10928-008-9090-8

Cite this article as:
Weiss, M. J Pharmacokinet Pharmacodyn (2008) 35: 325. doi:10.1007/s10928-008-9090-8

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

Keywords

ObesityThiopentalPharmacokineticsResidence timeRelative dispersionBody fatDistribution clearance

Glossary

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

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/Vbody

CLM

Whole body distribution clearance

Q

Cardiac output

i = F

Fat tissue

i = NF

Nonfat tissue

Qi

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

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

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

Vi

Physiological volume of tissue i

bf

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

Vss

Volume of distribution at steady-state

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

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

Vz

Terminal distribution volume

t1/2,z

Terminal half-live

Download to read the full article text

Copyright information

© Springer Science+Business Media, LLC 2008