Vitamin D deficiency (VDD) is common in women with and without polycystic ovary syndrome (PCOS) and may be associated with metabolic and endocrine disorders in PCOS. The aim of this meta-analysis is to assess the associations of serum vitamin D levels with metabolic and endocrine dysregulations in women with PCOS, and to determine effects of vitamin D supplementation on metabolic and hormonal functions in PCOS patients. The literature search was undertaken through five databases until 16 January 2015 for both observational and experimental studies concerning relationships between vitamin D and PCOS. A total of 366 citations were identified, of which 30 were selected (n = 3182). We found that lower serum vitamin D levels were related to metabolic and hormonal disorders in women with PCOS. Specifically, PCOS patients with VDD were more likely to have dysglycemia (e.g., increased levels of fasting glucose and homeostatic model assessment-insulin resistance index (HOMA-IR)) compared to those without VDD. This meta-analysis found no evidence that vitamin D supplementation reduced or mitigated metabolic and hormonal dysregulations in PCOS. VDD may be a comorbid manifestation of PCOS or a minor pathway in PCOS associated metabolic and hormonal dysregulation. Future prospective observational studies and randomized controlled trials with repeated VDD assessment and better characterization of PCOS disease severity at enrollment are needed to clarify whether VDD is a co-determinant of hormonal and metabolic dysregulations in PCOS, represents a consequence of hormonal and metabolic dysregulations in PCOS or both.

Numerous studies have engineered nanoparticles with different physicochemical properties to enhance the delivery efficiency to solid tumors, yet the mean and median delivery efficiencies are only 1.48% and 0.70% of the injected dose (%ID), respectively, according to a study using a nonphysiologically based modeling approach based on published data from 2005 to 2015. In this study, we used physiologically based pharmacokinetic (PBPK) models to analyze 376 data sets covering a wide range of nanomedicines published from 2005 to 2018 and found mean and median delivery efficiencies at the last sampling time point of 2.23% and 0.76%ID, respectively. Also, the mean and median delivery efficiencies were 2.24% and 0.76%ID at 24 h and were decreased to 1.23% and 0.35%ID at 168 h, respectively, after intravenous administration. While these delivery efficiencies appear to be higher than previous findings, they are still quite low and represent a critical barrier in the clinical translation of nanomedicines. We explored the potential causes of this poor delivery efficiency using the more mechanistic PBPK perspective applied to a subset of gold nanoparticles and found that low delivery efficiency was associated with low distribution and permeability coefficients at the tumor site (P < 0.01). We also demonstrate how PBPK modeling and simulation can be used as an effective tool to investigate tumor delivery efficiency of nanomedicines.

Nanoparticles (NPs) are widely used in various fields of nanomedicine. A systematic understanding of NP pharmacokinetics is crucial in their design, applications, and risk assessment. In order to integrate available experimental information and to gain insights into NP pharmacokinetics, a membrane-limited physiologically based pharmacokinetic (PBPK) model for polyethylene glycol-coated gold (Au) NPs (PEG-coated AuNPs) was developed in mice. The model described endocytosis of the NPs in the liver, spleen, kidneys, and lungs and was calibrated using data from mice that were intravenously injected with 0.85 mg/kg 13 nm and 100 nm PEG-coated AuNPs. The model adequately predicted multiple external datasets for PEG-coated AuNPs of similar sizes (13-20 nm; 80-100 nm), indicating reliable predictive capability in suitable size ranges. Simulation results suggest that endocytosis of NPs is time and size dependent, i.e. endocytosis of larger NPs occurs immediately and predominately from the blood, whereas smaller NPs can diffuse through the capillary wall and their endocytosis appears mainly from the tissue with a 10-h delay, which may be the primary mechanism responsible for the reported size-dependent pharmacokinetics of NPs. Several physiological parameters (e.g. liver weight fraction of body weight) were identified to have a high influence on selected key dose metrics, indicating the need for additional interspecies comparison and scaling studies and to conduct pharmacokinetic studies of NPs in species that are more closely related to humans in these parameters. This PBPK model provides useful insights into the size, time, and species dependence of NP pharmacokinetics.

Metallic nanoparticles (NPs) have been widely applied in the field of nanomedicine. A comprehensive understanding of their pharmacokinetics is crucial for proper risk assessment and safe biomedical applications. This review focuses on gold and silver (Ag) NPs, and briefly discusses iron oxide, titanium dioxide (TiO2 ), and zinc oxide NPs. Pharmacokinetics of metallic NPs depends on the particle type, size, surface charge, surface coating, protein binding, exposure route, dose, and species. Generally, blood half-life is shorter in rodents than in larger laboratory animals (e.g., rabbits or monkeys) and differs between intravenous and oral exposures. Oral, dermal, or inhalational absorption is low (≤5%), but may increase with smaller sizes, negative charge, and appropriate coatings. Metallic NPs can be distributed throughout the body, primarily accumulating in the liver, spleen, and lymph node due to nonspecific uptake by reticuloendothelial cells, and could remain in the body for ≥6 months. Metallic NPs (≤100 nm) can cross the blood-brain barrier (BBB), favored by coating with BBB-permeable neuropeptides. Placental transfer depends on the stage of embryonic/placental maturation and surface composition, and may be enhanced by coating with biocompatible molecules (e.g., ferritin or polyethylene glycol). Renal and biliary excretion is generally low due to persistent accumulation in tissues, but renal elimination could be substantially increased with smaller sizes and specific coatings (e.g., glutathione). Physiologically based pharmacokinetic models for gold/dendrimer composite nanodevices, AgNPs, and TiO2 NPs have been developed in rats and the AgNP and TiO2 NP models have been extrapolated to humans to support risk assessment and nanomedicine applications.

This review provides a tutorial for individuals interested in quantitative veterinary pharmacology and toxicology and offers a basis for establishing guidelines for physiologically based pharmacokinetic (PBPK) model development and application in veterinary medicine. This is important as the application of PBPK modeling in veterinary medicine has evolved over the past two decades. PBPK models can be used to predict drug tissue residues and withdrawal times in food-producing animals, to estimate chemical concentrations at the site of action and target organ toxicity to aid risk assessment of environmental contaminants and/or drugs in both domestic animals and wildlife, as well as to help design therapeutic regimens for veterinary drugs. This review provides a comprehensive summary of PBPK modeling principles, model development methodology, and the current applications in veterinary medicine, with a focus on predictions of drug tissue residues and withdrawal times in food-producing animals. The advantages and disadvantages of PBPK modeling compared to other pharmacokinetic modeling approaches (i.e., classical compartmental/noncompartmental modeling, nonlinear mixed-effects modeling, and interspecies allometric scaling) are further presented. The review finally discusses contemporary challenges and our perspectives on model documentation, evaluation criteria, quality improvement, and offers solutions to increase model acceptance and applications in veterinary pharmacology and toxicology.

These results partially explain the current low translation rate of nanotechnology-based drug delivery systems from mice to humans. This simulation approach may be applied to other nanomaterials and provides guidance to design future translational studies.

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Physiologically based pharmacokinetic (PBPK) models for chemicals in food animals are a useful tool in estimating chemical tissue residues and withdrawal intervals. Physiological parameters such as organ weights and blood flows are an important component of a PBPK model. The objective of this study was to compile PBPK‐related physiological parameter data in food animals, including cattle and swine. Comprehensive literature searches were performed in PubMed, Google Scholar, ScienceDirect, and ProQuest. Relevant literature was reviewed and tables of relevant parameters such as relative organ weights (% of body weight) and relative blood flows (% of cardiac output) were compiled for different production classes of cattle and swine. The mean and standard deviation of each parameter were calculated to characterize their variability and uncertainty and to allow investigators to conduct population PBPK analysis via Monte Carlo simulations. Regression equations using weight or age were created for parameters having sufficient data. These compiled data provide a comprehensive physiological parameter database for developing PBPK models of chemicals in cattle and swine to support animal‐derived food safety assessment. This work also provides a basis to compile data in other food animal species, including goats, sheep, chickens, and turkeys.