Journal of Pharmacokinetics and Pharmacodynamics

, Volume 35, Issue 1, pp 31–68

Development of a human physiologically based pharmacokinetic (PBPK) model for inorganic arsenic and its mono- and di-methylated metabolites

Article

DOI: 10.1007/s10928-007-9075-z

Cite this article as:
El-Masri, H.A. & Kenyon, E.M. J Pharmacokinet Pharmacodyn (2008) 35: 31. doi:10.1007/s10928-007-9075-z

Abstract

A physiologically-based pharmacokinetic (PBPK) model was developed to estimate levels of arsenic and its metabolites in human tissues and urine after oral exposure to arsenate (AsV), arsenite (AsIII) or organoarsenical pesticides. The model consists of interconnected individual PBPK models for inorganic arsenic (AsV and AsIII), monomethylarsenic acid (MMAV), and, dimethylarsenic acid (DMAV). Reduction of MMAV and DMAV to their respective trivalent forms also occurs in the lung, liver, and kidney including excretion in urine. Each submodel was constructed using flow limited compartments describing the mass balance of the chemicals in GI tract (lumen and tissue), lung, liver, kidney, muscle, skin, heart, and brain. The choice of tissues was based on physiochemical properties of the arsenicals (solubility), exposure routes, target tissues, and sites for metabolism. Metabolism of inorganic arsenic in liver was described as a series of reduction and oxidative methylation steps incorporating the inhibitory influence of metabolites on methylation. The inhibitory effects of AsIII on the methylation of MMAIII to DMA, and MMAIII on the methylation of AsIII to MMA were modeled as noncompetitive. To avoid the uncertainty inherent in estimation of many parameters from limited human data, a priori independent parameter estimates were derived using data from diverse experimental systems with priority given to data derived using human cells and tissues. This allowed the limited data for human excretion of arsenicals in urine to be used to estimate only parameters that were most sensitive to this type of data. Recently published urinary excretion data, not previously used in model development, are also used to evaluate model predictions.

Keywords

Arsenic Human PBPK MMA DMA 

Abbreviations

As

Inorganic arsenic

AsIII

Trivalent inorganic arsenic

AsV

Pentavalent inorganic arsenic

MMAIII

Monomethylarsonous acid

MMAV

Monomethylarsenic acid

DMAIII

Dimethylarsinous acid

DMAV

Dimethylarsinic acid

TMAO

Trimethylarsine oxide

PBPK

Physiologically based pharmacokinetic

AS3MT

Arsenic +3 oxidation state methyltransferase

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  1. 1.Experimental Toxicology Division, National Health and Environmental Effects Research LaboratoryU. S. Environmental Protection AgencyResearch Triangle ParkUSA

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