The Relationship Between Internal and External Dose: Some General Results Based on a Generic Compartmental Model.

Toxicological Sciences : an Official Journal of the Society of Toxicology
Wout SlobRudolf T Hoogenveen

Abstract

Statements on how the internal-to-external-dose (IED) relationship looks like are often based on qualitative toxicokinetic arguments. For example, the recently proposed kinetically derived maximum dose (KMD) states that the IED relationship must have an inflection point, due to saturation of underlying processes like metabolism or absorption. However, such statements lack a solid quantitative foundation. Therefore, we derived expressions for the IED relationship for a number of scenarios based on a generic compartmental model involving saturation. The scenarios included repeated or single dose, and saturable metabolism or saturable absorption. For some of these scenarios, an explicit expression for the IED relationship can be derived, for others only implicit expressions can be established, which need to be evaluated numerically. The results show that saturable processes will lead to an IED relationship that is nonlinear over the whole dose range, ie, it can be approximated by a linear relationship at the lower end, whereas the approximation will become gradually poorer with increasing doses. The finding that saturation does not lead to an inflection point in the IED relationship, as assumed in the KMD, implies that the KMD is ...Continue Reading

References

Nov 8, 2007·Toxicologic Pathology·Wout Slob
Dec 27, 2011·Regulatory Toxicology and Pharmacology : RTP·Stuart CretonKim Z Travis
Nov 21, 2013·Critical Reviews in Toxicology·Wout Slob, R Woodrow Setzer
Oct 17, 2015·Regulatory Toxicology and Pharmacology : RTP·Claire TerryDaland R Juberg
Apr 14, 2016·Regulatory Toxicology and Pharmacology : RTP·Shakil A Saghir, Michael A Dorato

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Citations

May 22, 2021·Regulatory Toxicology and Pharmacology : RTP·Anne E LoccisanoEric Fabian
Feb 2, 2022·Archives of Toxicology·Lyle D BurgoonChristopher J Borgert

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