Updating physiologically based pharmacokinetic models for manganese by incorporating rapid association/dissociation processes in tissues.

08:00 EDT 9th April 2019 | BioPortfolio

Summary of "Updating physiologically based pharmacokinetic models for manganese by incorporating rapid association/dissociation processes in tissues."

Previously, we developed a series of physiologically based pharmacokinetic (PBPK) models for manganese (Mn) in which saturable tissue binding and dose-dependent increases in biliary excretion captured key aspects of Mn homeostasis biology. These models reproduced the non-linear behavior of Mn kinetics in different tissues, accounting for dose-dependent changes in Mn kinetics. The original model construct had relatively slow association and dissociation rate constants for Mn binding in tissues. In this updated model, both rates of entry into tissue and the interaction of Mn with binding sites are rapid, and the step limiting Mn accumulation is the saturation of tissue binding sites. This binding reflects general cellular requirements for Mn with high affinity but rapid exchange between bound and free forms, which we captured using a dissociation constant (KD) of ~ 0.5 μM across tissues while maintaining different maximum binding capacities in each tissue. Variability in the binding capacities accounted for different background levels of Mn in particular tissues. This alternative structure successfully described Mn kinetics in tissues in adult rats exposed to Mn either in their diet or by inhalation, indicating that both the original and the present models capture the dose-dependent and tissue-specific kinetic behavior of Mn in adult rats. Although the published models that emphasize the role of smaller tissue binding rate constants in non-linear behaviors capture all relevant dose-dependent kinetic behaviors of this metal, increasing biological relevance of the model structure and parameters should provide greater confidence in applying the Mn PBPK models to risk assessment.


Journal Details

This article was published in the following journal.

Name: Toxicology and applied pharmacology
ISSN: 1096-0333


DeepDyve research library

PubMed Articles [22899 Associated PubMed Articles listed on BioPortfolio]

Physiologically Based Pharmacokinetic Modeling for Trimethoprim and Sulfamethoxazole in Children.

The aims of this study were to (1) determine whether opportunistically collected data can be used to develop physiologically based pharmacokinetic (PBPK) models in pediatric patients; and (2) characte...

Evaluation of the predictive performance of physiologically based pharmacokinetic models for intramuscular injections of therapeutic proteins.

Several physiologically-based pharmacokinetic (PBPK) models have been reported for intravenous (IV) and subcutaneous (SC) injections, but there has been a paucity of work for intramuscular (IM) inject...

Correction to "Plasma and Hepatic Concentrations of Chemicals after Virtual Oral Administrations Extrapolated Using Rat Plasma Data and Simple Physiologically Based Pharmacokinetic Models".

Application of Physiologically-Based Pharmacokinetic Modeling to Predict Pharmacokinetics in Healthy Japanese Subjects.

Pharmacokinetics (PK) in Japanese healthy subjects were simulated for nine compounds using physiologically based pharmacokinetic (PBPK) models parameterized with physicochemical properties, preclinica...

Physiologically based pharmacokinetic modeling to supplement nilotinib pharmacokinetics and confirm dose selection in pediatric patients.

In adult patients nilotinib is indicated for chronic myeloid leukemia at an approved oral dose of 300 or 400 mg BID. Physiologically based pharmacokinetic (PBPK) model was developed to describe and su...

Clinical Trials [7359 Associated Clinical Trials listed on BioPortfolio]

Physiologically-based Pharmacokinetic Modeling of Ivermectin in Healthy Human Volunteers

The present study assesses the pharmacokinetic profile of Ivermectin (IVM) in healthy human volunteers and aims to create a physiologically-based pharmacokinetic model. Planned indication ...

Manganese in Women With Encephalopathy

Objective: Report manganese serum levels and mortality in encephalopathic patients. Patients and participants: Consecutive patients aged > 18 years, with hepatic encephalopathy an...

Cognitive Training in Parkinson's Disease, the iPARK Study

The aim of the iPARK-study is to investigate the effects of a process-based cognitive training program with focus on working memory in patients with Parkinson's Disease (PD). The study is ...

PK of Clindamycin and Trimethoprim-sulfamethoxazole in Infants and Children

Developmental changes in physiology during childhood influence drug dosing. Failure to account for these changes leads to improper dosing, which is associated with decreased drug efficacy ...

Rapid Prototyping Models for Patient Education

Pre-made rapid prototyping models will be used to increase patient education versus current methodologies.

Medical and Biotech [MESH] Definitions

Manganese poisoning is associated with chronic inhalation of manganese particles by individuals who work with manganese ore. Clinical features include CONFUSION; HALLUCINATIONS; and an extrapyramidal syndrome (PARKINSON DISEASE, SECONDARY) that includes rigidity; DYSTONIA; retropulsion; and TREMOR. (Adams, Principles of Neurology, 6th ed, p1213)

Inorganic chemicals that contain manganese as an integral part of the molecule.

Theoretical representations that simulate the behavior or activity of biological processes or diseases. For disease models in living animals, DISEASE MODELS, ANIMAL is available. Biological models include the use of mathematical equations, computers, and other electronic equipment.

Statistical models in which the value of a parameter for a given value of a factor is assumed to be equal to a + bx, where a and b are constants. The models predict a linear regression.

Statistical models of the production, distribution, and consumption of goods and services, as well as of financial considerations. For the application of statistics to the testing and quantifying of economic theories MODELS, ECONOMETRIC is available.

Quick Search


DeepDyve research library

Relevant Topic

Biological Therapy
Biological therapy involves the use of living organisms, substances derived from living organisms, or laboratory-produced versions of such substances to treat disease. Some biological therapies for cancer use vaccines or bacteria to stimulate the body&rs...

Searches Linking to this Article