Physiologically Based Pharmacokinetic Model for Chronic Inhalation of 2-Butoxyethanol
22
Citation
52
Reference
10
Related Paper
Citation Trend
Keywords:
Toxicodynamics
Inhalation exposure
Pharmacodynamics
This chapter contains sections titled: Introduction Benchmark Dose Toxicokinetics In Vivo Basics of In Vitro Toxicodynamics Rationale Describing In Vitro Toxicokinetics and Dynamics and Aim of the Present Study In Vitro Toxicokinetics and Dynamics Concluding Remarks Regarding the Eight Models of Toxicity and the Discrimination Between Them Acknowledgment References
Toxicodynamics
Cite
Citations (3)
Toxicodynamics
Xenobiotic
Pharmacodynamics
Cite
Citations (4)
Toxicodynamics
Inhalation exposure
Pharmacodynamics
Cite
Citations (22)
Toxicodynamics
Cite
Citations (0)
A multi-compartment physiologically based pharmacokinetic (PBPK) model was developed to describe the behavior of Cr(III) and Cr(VI) in humans. Compartments were included for gastrointestinal lumen, oral mucosa, stomach, small intestinal tissue, blood, liver, kidney, bone, and a combined compartment for remaining tissues. As chronic exposure to high concentrations of Cr(VI) in drinking water cause small intestinal cancer in mice, the toxicokinetics of Cr(VI) in the upper gastrointestinal tract of rodents and humans are important for assessing internal tissue dose in risk assessment. Fasted human stomach fluid was collected and ex vivo Cr(VI) reduction studies were conducted and used to characterize reduction of Cr(VI) in human stomach fluid as a mixed second-order, pH-dependent process. For model development, toxicokinetic data for total chromium in human tissues and excreta were identified from the published literature. Overall, the PBPK model provides a good description of chromium toxicokinetics and is consistent with the available total chromium data from Cr(III) and Cr(VI) exposures in typical humans (i.e., model predictions are within a factor of three for approximately 86% of available data). By accounting for key species differences, sources of saturable toxicokinetics, and sources of uncertainty and variation, the rodent and human PBPK models can provide a robust characterization of toxicokinetics in the target tissue of the small intestine allowing for improved health risk assessment of human populations exposed to environmentally-relevant concentrations.
Ex vivo
Cite
Citations (40)
Hexabromocyclododecane
Cite
Citations (12)
Toxicodynamics
Xenobiotic
Toxicant
Cite
Citations (1)
Abstract Knowledge about toxicokinetics and toxicodynamics is of crucial importance for various areas of pharmaceutical research. Toxicokinetics is generally regarded as an area of science that deals with kinetics of exposure, absorption, distribution, metabolism, and excretion of test compounds and metabolites. This article describes in vitro concentration‐effect relationships and also discusses tools to elucidate the toxicomechanisms under in vitro conditions.
Toxicodynamics
Cite
Citations (1)
Toxicodynamics
Cite
Citations (84)
The importance of toxicokinetics in the drug development has been identified in the last decade. The main objectives of toxicokinetics in general are to define the drug bioavailability, dose proportionality, gender differences, and species differences in pharmacokinetics and metabolism, from which the target organ toxicity can be predicted and the safety doses in the first human clinical trial can be established. Toxicokinetic studies may also serve as a tool for the toxicologic pathologist in understanding models used for predicting and assessing drug-related toxic response. Toxicokinetics/toxicodynamics are critical to investigating the toxicological mechanism and understanding the comparative toxicity between animals and humans. This report presents an overview of the application of toxicokinetics and its impact in the drug development of PNU-101017, a drug candidate for the treatment of anxioety. Serial specifically designed toxicokinetic studies identified a steep dose-response relationship between the clinical signs and PNU-101017 serum or CSF concentrations, characterized the centrally mediated respiratory depression as the toxicity leading to the lethality, and demonstrated marked species differences in the sensitivity to the toxic effects. These findings lead to a termination of PNU-101017 development due to the safety concern in humans.
Toxicodynamics
Drug Development
Cite
Citations (9)