Absorption, Distribution, Metabolism And Excretion Processes Research Articles

Genetic studies of urinary metabolites illuminate mechanisms of detoxification and excretion in humans.

The kidneys integrate information from continuous systemic processes related to the absorption, distribution, metabolism and excretion (ADME) of metabolites. To identify underlying molecular mechanisms, we performed genome-wide association studies of the urinary concentrations of 1,172 metabolites among 1,627 patients with reduced kidney function. The 240 unique metabolite-locus associations (metabolite quantitative trait loci, mQTLs) that were identified and replicated highlight novel candidate substrates for transport proteins. The identified genes are enriched in ADME-relevant tissues and cell types, and they reveal novel candidates for biotransformation and detoxification reactions. Fine mapping of mQTLs and integration with single-cell gene expression permitted the prioritization of causal genes, functional variants and target cell types. The combination of mQTLs with genetic and health information from 450,000 UK Biobank participants illuminated metabolic mediators, and hence, novel urinary biomarkers of disease risk. This comprehensive resource of genetic targets and their substrates is informative for ADME processes in humans and is relevant to basic science, clinical medicine and pharmaceutical research.

Development and prospect of biological effects and safety of nanomaterials

Nanomaterials have lots of unique physical and chemical properties, such as quantum size effect, surface effect and macroscopic quantum tunnel effect. The biological effects of nanomaterials might be different from those of bulk materials larger than microns even if their chemical compositions are same. Therefore, the biological effects and safety evaluation results obtained from the bulk materials might not be suitable for the nanomaterials. Since 2003, governments worldwide have initiated the researches on biological effects and safety issues of nanomaterials with increasing financial support. China is one of the earliest countries in the world to carry out researches on biological effects and safety issues of nanomaterials. And some research fields have entered the forefront of the world. The CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety established jointly by National Center for Nanoscience and Technology (NCNST) and Institute of High Energy Physics of Chinese Academy of Sciences (IHEP of CAS) was the first professional laboratory focusing on the biological effects and safety of nanomaterials in China. Scientists in this laboratory have done many in-depth studies of the relationship between the physical-chemical properties and biological responses of nanomaterials. They found several factors which affected the biological effects of carbon nanotubes significantly, such as nanoparticle-Crona, metal impurities, surface, size, shape and so on. They have also established multiple models for hazard recognition and risk assessment. Nanomaterials/nanoparticles (NMs/NPs) are exposed to human beings mostly through four routes, i.e., oral intake, skin contact, inhalation, and intravenous injection. Upon entering the body, NMs/NPs are quickly distributed into specific organs and then metabolized primarily by the liver. The final excretion of NMs/NPs usually occurs in the liver and kidney in the form of urine and feces. In general, the most important issues regarding the absorption, distribution, metabolism and excretion (ADME) processes of NMs/NPs include: (1) Where do and how much NMs/NPs get in (via absorption)? (2) Where do and how much NMs/NPs go (via distribution)? (3) How much, when do, and what form of NMs/NPs remain intact (via metabolism)? (4) Where do, how much, and what form of NMs/NPs stay in the system (via excretion)? At various stages of the ADME processes, the challenges for in vivo analysis of NMs/NPs may become largely different. Important analytical methods to resolve the analytical challenges for each absorption, distribution, metabolism and excretion (ADME) process are summarized. The state-of-the art techniques with high sensitivity and high resolution suitable for safety evaluation have been developed to ensure the sustainable development of nanotechnology, such as inductively coupled plasma mass spectrometry (ICPMS), inductively coupled plasma optical emission spectrometry (ICP-OES), nuclear analysis such as neutron activation analysis (NAA), laser ablation inductively coupled plasma mass spectrometry (LAICPMS), secondary ion mass spectrometry (SIMS), synchrotron radiation X-ray fluorescence spectroscopy (SRXRF), X-ray absorption spectroscopy (XAS), X-ray fluorescence spectroscopy (XRF), scanning transmission X-ray microscopy (STXM), transmission X-ray microscopy (TXM) and so on. In this review, we summarize these research progresses in recent years.

Application of physiologically based toxicokinetics models in risk assessment of chemicals

External exposure concentrations were conventionally employed used to quantify toxicological effects of chemicals in their risk assessment. However, internal concentrations are more suitable for understanding the toxicological effects and conducting risk assessment. It is necessary for accurate risk assessment of chemicals to predict the internal exposure of chemicals from the external exposure, and to know distribution of chemicals in different target tissues/organs (e.g. liver, kidney) of organisms. Experimental determination can hardly get high-throughput acquisition of target concentrations due to analytical limitations and expensive cost for in vivo animal tests. Alternatively, physiologically based toxicokinetics (PBTK) models that can quantitatively predict absorption, distribution, metabolism and excretion (ADME) processes of chemicals in biota are particularly useful. PBTK models could be used to predict the target concentrations, and to relate the environmental exposure concentrations with the target concentrations. Development of PBTK models can be divided into five steps. (1) Specify the general model structure. Portal of entry, target organ, lipophilicity and metabolism of chemicals are basic factors that should be considered. (2) Determine the set of ordinary differential equations representing the ADME processes of chemicals by the organism. All of these equations are mass balance equations. (3) Define model parameters, including physiological parameters, partition coefficients, biochemical rate constants and environment parameters. (4) Solve the ordinary differential equations with proper software. (5) Validate the model. Simulation results should be compared with corresponding experimental data to evaluate whether the model is accurate enough. Sensitivity, uncertainty and variability analysis should be performed to further optimize the model. Originating as a tool for serving pharmaceutical industry, PBTK models are now used in risk assessment of chemicals. PBTK models can also relate the in vivo toxicity thresholds with the in vitro toxicity thresholds. The in vitro-in vivo extrapolation can facilitate the utilization of the vast volume of high-throughput in vitro data. Traditional in vivo tests only focus on a limited number of the diverse species residing within an ecosystem. PBTK models can provide a promising cross-species solution by establishing physiologically relevant models for various species. Besides, classical indicators for hazard assessment such as bioconcentration factors could be re-evaluated by PBTK models with upgraded accuracy and details. Furthermore, it is possible to simulate the risk of chemicals that exerted on organisms over the entire lifetime of organisms with a sequence of PBTK models representing different developmental stages of the species. The combination of PBTK models and toxicodynamics (TD) models, i.e. PBTK/TD models, can further realize the simulation of the dynamic distribution of xenobiotics as well as the effects simultaneously. The power of PBTK models intended for ecological risk assessment of chemicals is yet to be fully exploited. Current PBTK models mainly apply to chemicals of neutral states. However, the molecular structures of many organic pollutants have carboxylic, phenolic groups, etc. Thus, these compounds can ionize under environmental pH conditions. A compound with different ionized states could possess different intake pathways. Thus, certain modifications of the mathematical form of the PBTK models are necessary. Another major obstacle is that the sophisticated parameters of PBTK models cannot be easily collected. Therefore, schemes for a high-throughput acquisition of the relevant parameters (e.g. quantitative structure-activity relationship models) would be highly useful. Furthermore, PBTK models should be extended to more species of ecological importance.

ADME Properties of Herbal Medicines in Humans: Evidence, Challenges and Strategies

Herbal medicines, an important group of multicomponent therapeutics, are widely and increasignly used worldwide. Despite the popularitiy of herbal medicines, the clinical evidence that support the use of most herbal medicines is weak. Pharmacokinetic and absorption, distribution, metabolism and excretion (ADME) studies have been integrated into modern drug development, but ADME studies are generally not needed for herbal remedy discovery and development. For the majority of herbal medicines, data on their ADME and pharmacokinetic properties in humans are lacking or scant. An extensive literature search indicates that there are limited data on ADME properties of herbal medicines in humans. Many herbal compounds undergo Phase I and/or Phase II metabolism in vivo, with cytochrome P450s (CYPs) and uridine diphosphate glucuronosyltransferases (UGTs) playing a major role. Some herbal ingredients are substrates of P-glycoprotein (P-gp/MDR1/ABCB1) which is highly expressed in the intestine, liver, brain and kidney. As such, the activities of these drug metabolizing enzymes and drug transporters are critical determining factors for the in vivo ADME processes of herbal remedies. There are increasing ADME studies of herbal remedies, but these studies are mainly focused on a small number of herbal medicines including St John's wort, milk thistle, curcumin, echinacea, ginseng, ginkgo, and ginger. For an herbal medicine, the pharmacological activity is gained when the active agents or the active metabolites reach and sustain proper levels at their sites of action. Both the dose levels and ADME processes of active herbal components in the body govern their target-site concentrations and thus the therapeutic responses. In this regard, a safe and optimal use of herbal medicines requires a full understanding of their ADME profiles. To optimize the use of herbal remedies, further studies to explore their ADME properties in humans are certainly warranted.

Pharmacokinetics of Biotech Drugs: Peptides, Proteins and Monoclonal Antibodies

With the advances in recombinant DNA biotechnology, molecular biology and immunology, the number of biotech drugs, including peptides, proteins and monoclonal antibodies, available for clinical use has dramatically increased in recent years. Although pharmacokinetic principles are equally applicable to the large molecule drugs and conventional small molecule drugs, the underlying mechanisms for the processes of absorption, distribution, metabolism and excretion (ADME) of large molecule drugs are often very different from that of small molecule drugs. Therefore, a good understanding of the ADME processes of large molecule drugs is essential in support of the development of therapeutic biologics. The purpose of this article is to review the current knowledge of the ADME processes that govern the pharmacokinetics of biotech drugs. The challenges encountered by orally administered peptide and protein drugs, and the nature of lymphatic absorption after subcutaneous administration will be discussed. In addition, molecular mechanisms of biodistribution, metabolism and renal excretion of biotech drugs will also be discussed. Finally, approaches used for prediction of human pharmacokinetics of protein drugs will be briefly discussed.

What do we (need to) know about the kinetic properties of nanoparticles in the body?

Nowadays the development and applications of nanotechnology are of major importance in both industrial and consumer areas. However, the knowledge on human exposure and possible toxicity of nanotechnology products is limited. To understand the mechanism of toxicity, thorough knowledge of the toxicokinetic properties of nanoparticles is warranted. There is a need for information on the absorption, distribution, metabolism and excretion (ADME) of nanoparticles and validated detection methods of these man-made nanoparticles. Determination of the ADME properties of nanoparticles requires specialised detection methods in different biological matrices (e.g. blood and organs). In this paper, the current knowledge on the kinetic properties of nanoparticles is reviewed. Moreover, knowledge gaps from a kinetic point of view (detection, dose, ADME processes) are identified.

Development and Application of Physiologically Based Pharmacokinetic-Modeling Tools to Support Drug Discovery

Physiologically based pharmacokinetic (PBPK) modeling integrates physicochemical (PC) and in vitro pharmacokinetic (PK) data using a mechanistic framework of principal ADME (absorption, distribution, metabolism, and excretion) processes into a physiologically based whole-body model. Absorption, distribution, and clearance are modeled by combining compound-specific PC and PK properties with physiological processes. Thereby, isolated in vitro data can be upgraded by means of predicting full concentration-time profiles prior to animal experiments. The integrative process of PBPK modeling leads to a better understanding of the specific ADME processes driving the PK behavior in vivo, and has the power to rationally select experiments for a more focussed PK project support. This article presents a generic disposition model based on tissue-composition-based distribution and directly scaled hepatic clearance. This model can be used in drug discovery to identify the critical PK issues of compound classes and to rationally guide the optimization path of the compounds toward a viable development candidate. Starting with a generic PBPK model, which is empirically based on the most common PK processes, the model will be gradually tailored to the specifics of drug candidates as more and more experimental data become available. This will lead to a growing understanding of the 'drug in the making', allowing a range of predictions to be made for various purposes and conditions. The stage is set for a wide penetration of PK modeling and simulations to form an intrinsic part of a project starting from lead discovery, to lead optimization and candidate selection, to preclinical profiling and clinical trials.