A Quantitative Structure-toxicokinetic Relationship Model for Highly Metabolised Chemicals

Patrick Poulin and Kannan Krishnan

The aim of the present study was to develop a quantitative structure-toxicokinetic relationship (QSTkR) model for highly metabolised chemicals (HMCs). The proposed QSTkR model is essentially a physiologically based toxicokinetic (PBTK) model, in which the blood:air and tissue:blood partition coefficients (PCs) are predicted from the molecular structure of chemicals, and the liver blood flow rate (Ql) is used to describe hepatic clearance. Molecular structure-based prediction of the blood:air and tissue:blood PCs was performed from the n-octanol:water and water:air PCs of chemicals obtained with the conventional fragment constant methods. The validity of incorporating Ql instead of metabolic rate constants, as the hepatic clearance factor, in PBTK models for HMCs (extraction ratio > 0.7) was verified by comparing the simulations of venous blood concentration (Cv) profiles obtained with both the QSTkR and PBTK model approaches for 1,1-dichloroethylene, trichloroethylene and furan in the rat. Following the validation of this alternative approach for describing hepatic clearance of HMCs, a QSTkR model for dichloromethane was constructed. This model used molecular structure information as the sole input, and provided simulations of Cv for human exposure to low concentrations of dichloromethane. The QSTkR model simulations were similar to those obtained with the previously validated, conventional human PBTK model with experimentally determined PCs and metabolic rate constants (Vmax, Km and Kf) for dichloromethane. The present methodology is the first validated example of a mechanistically based prediction of the inhalation toxicokinetics of HMCs made solely from information on molecular structure.
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MEIC Evaluation of Acute Systemic Toxicity

Björn Ekwall, Cecilia Clemedson, Balcarras Crafoord

The Multicenter Evaluation of In Vitro Cytotoxicity (MEIC) programme was set up to evaluate the relevance for acute human systemic toxicity of in vitro cytotoxicity tests. At the end of the programme in the summer of 1996, 29 laboratories had tested all 50 reference chemicals in 61 cytotoxicity assays. As a necessary prerequisite to the forthcoming evaluation papers of this series, this paper presents the animal and human toxicity data of the programme. This database contains tabulated handbook data for the 50 chemicals, on: a) oral rat and mouse LD50 values; b) acute oral lethal doses in humans; c) clinically measured acute lethal serum concentrations in humans; d) acute lethal blood concentrations in humans measured postmortem; e) peaks from curves of an approximate 50% lethal blood/serum concentration over time after ingestion (LC50 curves), derived from a compilation of human acute poisoning case reports; f) human kinetics of single doses, including absorption, peak time, distribution/elimination curve, plasma half-life, distribution volume, distribution to organs (notably brain), and blood protein binding; and g) qualitative human acute toxicity data, including lethal symptoms, main causes of death, average time to death, target organs, presence of histopathological injury in target organs, presence of toxic metabolites, and known or hypothetical mechanisms for the lethal toxicity. The rationales for selection of the human toxicity data are also noted. The methods used to compile the in vivo toxicity data are described, including a presentation of a new method of constructing LC50 curves. Finally, the merits and shortcomings of the various human toxicity data for evaluation purposes are discussed.
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Physiologically-based Simulation Modelling for the Reduction of Animal Use in the Discovery of Novel Pharmaceuticals

Simon Thomas

The global pharmaceutical industry is estimated to use close to 20 million animals annually, in in vivo studies which apply the results of fundamental biomedical research to the discovery and development of novel pharmaceuticals, or to the application of existing pharmaceuticals to novel therapeutic indications. These applications of in vivo experimentation include: a) the use of animals as disease models against which the efficacy of therapeutics can be tested; b) the study of the toxicity of those therapeutics, before they are administered to humans for the first time; and c) the study of their pharmacokinetics — i.e. their distribution throughout, and elimination from, the body. In vivo pharmacokinetic (PK) studies are estimated to use several hundred thousand animals annually. The success of pharmaceutical research currently relies heavily on the ability to extrapolate from data obtained in such in vivo studies to predict therapeutic behaviour in humans. Physiologically-based modelling has the potential to reduce the number of in vivo animal studies that are performed by the pharmaceutical industry. In particular, the technique of physiologically-based pharmacokinetic (PBPK) modelling is sufficiently developed to serve as a replacement for many in vivo PK studies in animals during drug discovery. Extension of the technique to incorporate the prediction of in vivo therapeutic effects and/or toxicity is less well-developed, but has potential in the longer-term to effect a significant reduction in animal use, and also to lead to improvements in drug discovery via the increased rationalisation of lead optimisation.
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