A unified algorithm for predicting partition coefficients for PBPK modeling of drugs and environmental chemicals

Journal Article · Wed Dec 15 00:00:00 EST 2010 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/j.taap.2010.09.010· OSTI ID:21529103

Peyret, Thomas ^[1]; Poulin, Patrick ^[2]; Krishnan, Kannan ^[3]

---

1. DSEST, Universite de Montreal, Canada H3T 1A8 (Canada)
2. Consultant, 4009 rue Sylvia Daoust, Quebec City, Quebec, G1X 0A6 (Canada)
3. DSEST, Universite de Montreal, H3T 1A8 (Canada)

The algorithms in the literature focusing to predict tissue:blood PC (P{sub tb}) for environmental chemicals and tissue:plasma PC based on total (K{sub p}) or unbound concentration (K{sub pu}) for drugs differ in their consideration of binding to hemoglobin, plasma proteins and charged phospholipids. The objective of the present study was to develop a unified algorithm such that P{sub tb}, K{sub p} and K{sub pu} for both drugs and environmental chemicals could be predicted. The development of the unified algorithm was accomplished by integrating all mechanistic algorithms previously published to compute the PCs. Furthermore, the algorithm was structured in such a way as to facilitate predictions of the distribution of organic compounds at the macro (i.e. whole tissue) and micro (i.e. cells and fluids) levels. The resulting unified algorithm was applied to compute the rat P{sub tb}, K{sub p} or K{sub pu} of muscle (n = 174), liver (n = 139) and adipose tissue (n = 141) for acidic, neutral, zwitterionic and basic drugs as well as ketones, acetate esters, alcohols, aliphatic hydrocarbons, aromatic hydrocarbons and ethers. The unified algorithm reproduced adequately the values predicted previously by the published algorithms for a total of 142 drugs and chemicals. The sensitivity analysis demonstrated the relative importance of the various compound properties reflective of specific mechanistic determinants relevant to prediction of PC values of drugs and environmental chemicals. Overall, the present unified algorithm uniquely facilitates the computation of macro and micro level PCs for developing organ and cellular-level PBPK models for both chemicals and drugs.

• OSTI ID: 21529103
• Journal Information: Toxicology and Applied Pharmacology, Vol. 249, Issue 3; Other Information: DOI: 10.1016/j.taap.2010.09.010; PII: S0041-008X(10)00344-3; Copyright (c) 2010 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
ADIPOSE TISSUE
ALCOHOLS
AROMATICS
BILIARY TRACT
BLOOD PLASMA
CALCULATION METHODS
DRUGS
ETHERS
FORECASTING
HYDROCARBONS
LIVER
MUSCLES
PARTITION
RATS
SIMULATION
ANIMAL TISSUES
ANIMALS
BIOLOGICAL MATERIALS
BLOOD
BODY
BODY FLUIDS
CONNECTIVE TISSUE
DIGESTIVE SYSTEM
GLANDS
HYDROXY COMPOUNDS
MAMMALS
MATERIALS
ORGANIC COMPOUNDS
ORGANIC OXYGEN COMPOUNDS
ORGANS
RODENTS
VERTEBRATES