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Drug Metabolism and Disposition: the... Jun 2023The development of safe and effective medications requires a profound understanding of their pharmacokinetic (PK) and pharmacodynamic properties. PK studies have been... (Review)
Review
The development of safe and effective medications requires a profound understanding of their pharmacokinetic (PK) and pharmacodynamic properties. PK studies have been built through investigation of enzymes and transporters that drive drug absorption, distribution, metabolism, and excretion (ADME). Like many other disciplines, the study of ADME gene products and their functions has been revolutionized through the invention and widespread adoption of recombinant DNA technologies. Recombinant DNA technologies use expression vectors such as plasmids to achieve heterologous expression of a desired transgene in a specified host organism. This has enabled the purification of recombinant ADME gene products for functional and structural characterization, allowing investigators to elucidate their roles in drug metabolism and disposition. This strategy has also been used to offer recombinant or bioengineered RNA (BioRNA) agents to investigate the posttranscriptional regulation of ADME genes. Conventional research with small noncoding RNAs such as microRNAs (miRNAs) and small interfering RNAs has been dependent on synthetic RNA analogs that are known to carry a range of chemical modifications expected to improve stability and PK properties. Indeed, a novel transfer RNA fused pre-miRNA carrier-based bioengineering platform technology has been established to offer consistent and high-yield production of unparalleled BioRNA molecules from fermentation. These BioRNAs are produced and processed inside living cells to better recapitulate the properties of natural RNAs, representing superior research tools to investigate regulatory mechanisms behind ADME. SIGNIFICANCE STATEMENT: This review article summarizes recombinant DNA technologies that have been an incredible boon in the study of drug metabolism and PK, providing investigators with powerful tools to express nearly any ADME gene products for functional and structural studies. It further overviews novel recombinant RNA technologies and discusses the utilities of bioengineered RNA agents for the investigation of ADME gene regulation and general biomedical research.
Topics: DNA, Recombinant; MicroRNAs; RNA, Small Interfering; Metabolic Clearance Rate; Technology; Recombinant Proteins; Pharmacokinetics
PubMed: 36948592
DOI: 10.1124/dmd.122.001008 -
Journal of Pharmacokinetics and... Dec 2010Malcolm Rowland has greatly facilitated an understanding of drug structure-pharmacokinetic relationships using a physiological perspective. His view points, covering a... (Review)
Review
Malcolm Rowland has greatly facilitated an understanding of drug structure-pharmacokinetic relationships using a physiological perspective. His view points, covering a wide range of activities, have impacted on my own work and on my appreciation and understanding of our science. This overview summarises some of our parallel activities, beginning with Malcolm's work on the pH control of amphetamine excretion, his work on the disposition of aspirin and on the application of clearance concepts in describing the disposition of lidocaine. Malcolm also spent a considerable amount of time developing principles that define solute structure and transport/pharmacokinetic relationships using in situ organ studies, which he then extended to involve the whole body. Together, we developed a physiological approach to studying hepatic clearance, introducing the convection-dispersion model in which there was a spread in blood transit times through the liver accompanied by permeation into hepatocytes and removal by metabolism or excretion into the bile. With a range of colleagues, we then further developed the model and applied it to various organs in the body. One of Malcolm's special interests was in being able to apply this knowledge, together with an understanding of physiological differences in scaling up pharmacokinetics from animals to man. The description of his many other activities, such as the development of clearance concepts, application of pharmacokinetics to the clinical situation and using pharmacokinetics to develop new compounds and delivery systems, has been left to others.
Topics: Absorption; Animals; Biological Transport; Humans; Liver; Metabolic Clearance Rate; Permeability; Pharmaceutical Preparations; Pharmacokinetics; Pharmacology, Clinical; Technology Transfer; Tissue Distribution
PubMed: 21107662
DOI: 10.1007/s10928-010-9174-0 -
Pharmacological Research Sep 2023Organ-on-chip (OoC) technology has led to in vitro models with many new possibilities compared to conventional in vitro and in vivo models. In this review, the potential... (Review)
Review
Organ-on-chip (OoC) technology has led to in vitro models with many new possibilities compared to conventional in vitro and in vivo models. In this review, the potential of OoC models to improve the prediction of human oral bioavailability and intrinsic clearance is discussed, with a focus on the functionality of the models and the application in current drug development practice. Multi-OoC models demonstrating the application for pharmacokinetic (PK) studies are summarized and existing challenges are identified. Physiological parameters for a minimal viable platform of a multi-OoC model to study PK are provided, together with PK specific read-outs and recommendations for relevant reference compounds to validate the model. Finally, the translation to in vivo PK profiles is discussed, which will be required to routinely apply OoC models during drug development.
Topics: Humans; Models, Biological; Drug Development; Biological Availability; Microphysiological Systems
PubMed: 37473876
DOI: 10.1016/j.phrs.2023.106853 -
British Journal of Clinical Pharmacology Jan 2023The storm-like nature of the health crises caused by COVID-19 has led to unconventional clinical trial practices such as the relaxation of exclusion criteria. The...
AIMS
The storm-like nature of the health crises caused by COVID-19 has led to unconventional clinical trial practices such as the relaxation of exclusion criteria. The question remains: how can we conduct diverse trials without exposing subgroups of populations to potentially harmful drug exposure levels? The aim of this study was to build a knowledge base of the effect of intrinsic/extrinsic factors on the disposition of several repurposed COVID-19 drugs.
METHODS
Physiologically based pharmacokinetic (PBPK) models were used to study the change in the pharmacokinetics (PK) of drugs repurposed for COVID-19 in geriatric patients, different race groups, organ impairment and drug-drug interactions (DDIs) risks. These models were also used to predict epithelial lining fluid (ELF) exposure, which is relevant for COVID-19 patients under elevated cytokine levels.
RESULTS
The simulated PK profiles suggest no dose adjustments are required based on age and race for COVID-19 drugs, but dose adjustments may be warranted for COVID-19 patients also exhibiting hepatic/renal impairment. PBPK model simulations suggest ELF exposure to attain a target concentration was adequate for most drugs, except for hydroxychloroquine, azithromycin, atazanavir and lopinavir/ritonavir.
CONCLUSION
We demonstrate that systematically collated data on absorption, distribution, metabolism and excretion, human PK parameters, DDIs and organ impairment can be used to verify simulated plasma and lung tissue exposure for drugs repurposed for COVID-19, justifying broader patient recruitment criteria. In addition, the PBPK model developed was used to study the effect of age and ethnicity on the PK of repurposed drugs, and to assess the correlation between lung exposure and relevant potency values from in vitro studies for SARS-CoV-2.
Topics: Humans; Aged; COVID-19; SARS-CoV-2; Drug Interactions; Liver Diseases; Hydroxychloroquine; Models, Biological; Pharmacokinetics; Computer Simulation
PubMed: 33226664
DOI: 10.1111/bcp.14668 -
Environmental Health Perspectives Dec 1994Processes controlling the absorption, distribution, metabolism, excretion, and pharmacologic effects of drugs are likely to be immature or altered in neonates and... (Review)
Review
Processes controlling the absorption, distribution, metabolism, excretion, and pharmacologic effects of drugs are likely to be immature or altered in neonates and infants. Absorption may be affected by differences in gastric pH and stomach emptying rate. Low serum protein concentrations and higher body water composition can change drug distribution. Drug metabolism enzyme activity is typically reduced in the neonate, but rapidly develops over the first year of life. Renal excretion mechanisms are low at birth, but mature over a few months. Limited data are available on the pharmacodynamics of drugs; infants show greater sensitivity to d-tubocurarine. Developmental changes are rapid during the first weeks and months of life, thus requiring continual modification of drug dosage regimens designed for treating pediatric patients.
Topics: Body Composition; Drug Monitoring; Gastric Emptying; Humans; Infant; Infant, Newborn; Intestinal Absorption; Pharmacokinetics; Risk Assessment
PubMed: 7737034
DOI: 10.1289/ehp.94102s11107 -
Biomedicine & Pharmacotherapy =... Oct 2021Chrysin is a promising naturally occurring flavonoid mainly found in honey and propolis. Although chrysin's biological activities have been demonstrated and the... (Review)
Review
Chrysin is a promising naturally occurring flavonoid mainly found in honey and propolis. Although chrysin's biological activities have been demonstrated and the mechanism of actions has been determined using in vitro and in vivo models, results from the current clinical studies were largely negative. A potential reason for chrysin's low efficacy in humans is poor oral bioavailability. In this paper, we reviewed the preclinical and clinical pharmacokinetics studies of chrysin and analyzed the mechanism of poor in vivo efficacy with emphasis on its bioavailability and ADME mechanism. Low aqueous solubility, rapid metabolism mediated by UGTs and SULT, efficient excretion through efflux transporters including BCRP and MRP2 are the major reasons causing poor systemic bioavailability for chrysin. However, because of efficient enterohepatic recycling facilitated by phase II metabolism and efflux, chrysin's bioavailability in the low GI tract is high. Thus, chrysin can be ideal for treating diseases in the terminal ileum and colon (e.g., carcinoma, local infection) since it is localized in the lower GI tract with limited delivery to other organs.
Topics: Animals; Biological Availability; Flavonoids; Honey; Humans; Propolis; Solubility
PubMed: 34449320
DOI: 10.1016/j.biopha.2021.112080 -
PloS One 2020A pharmacogenomics-based pathway represents a series of reactions that occur between drugs and genes in the human body after drug administration. PG-path is a...
A pharmacogenomics-based pathway represents a series of reactions that occur between drugs and genes in the human body after drug administration. PG-path is a pharmacogenomics-based pathway that standardizes and visualizes the components (nodes) and actions (edges) involved in pharmacokinetic and pharmacodynamic processes. It provides an intuitive understanding of the drug response in the human body. A pharmacokinetic pathway visualizes the absorption, distribution, metabolism, and excretion (ADME) at the systemic level, and a pharmacodynamic pathway shows the action of the drug in the target cell at the cellular-molecular level. The genes in the pathway are displayed in locations similar to those inside the body. PG-path allows personalized pathways to be created by annotating each gene with the overall impact degree of deleterious variants in the gene. These personalized pathways play a role in assisting tailored individual prescriptions by predicting changes in the drug concentration in the plasma. PG-path also supports counseling for personalized drug therapy by providing visualization and documentation.
Topics: Computational Biology; Databases, Genetic; Drug Therapy; Drug-Related Side Effects and Adverse Reactions; Gastrointestinal Absorption; Genetic Association Studies; Humans; Inactivation, Metabolic; Information Storage and Retrieval; Metabolic Networks and Pathways; Models, Theoretical; Pharmaceutical Preparations; Pharmacogenetics; Precision Medicine; Software
PubMed: 32365122
DOI: 10.1371/journal.pone.0230950 -
British Journal of Clinical Pharmacology Apr 2021Mycophenolic acid (MPA) is widely used in paediatric kidney transplant patients and sometimes prescribed for additional indications. Population pharmacokinetic or... (Review)
Review
Mycophenolic acid (MPA) is widely used in paediatric kidney transplant patients and sometimes prescribed for additional indications. Population pharmacokinetic or pharmacodynamic modelling has been frequently used to characterize the fixed, random and covariate effects of MPA in adult patients. However, MPA population pharmacokinetic data in the paediatric population have not been systematically summarized. The objective of this narrative review was to provide an up-to-date critique of currently available paediatric MPA population pharmacokinetic models, with emphases on modelling techniques, pharmacological findings and clinical relevance. PubMed and EMBASE were searched from inception of database to May 2020, where a total of 11 studies have been identified representing kidney transplant (n = 4), liver transplant (n = 1), haematopoietic stem cell transplant (n = 1), idiopathic nephrotic syndrome (n = 2), systemic lupus erythematosus (n = 2), and a combined population consisted of kidney, liver and haematopoietic stem cell transplant patients (n = 1). Critical analyses were provided in the context of MPA absorption, distribution, metabolism, excretion and bioavailability in this paediatric database. Comparisons to adult patients were also provided. With respect to clinical utility, Bayesian estimation models (n = 6) with acceptable accuracy and precision for MPA exposure determination have also been identified and systematically evaluated. Overall, our analyses have identified unique features of MPA clinical pharmacology in the paediatric population, while recognizing several gaps that still warrant further investigations. This review can be used by pharmacologists and clinicians for improving MPA pharmacokinetic-pharmacodynamic modelling and patient care.
Topics: Adult; Area Under Curve; Bayes Theorem; Biological Availability; Child; Humans; Immunosuppressive Agents; Kidney Transplantation; Mycophenolic Acid
PubMed: 33118201
DOI: 10.1111/bcp.14590 -
Nature Materials May 2019A recent conference organized a panel of scientists representing small and big pharma companies, who work at the interface of machine learning (ML) and absorption,...
A recent conference organized a panel of scientists representing small and big pharma companies, who work at the interface of machine learning (ML) and absorption, distribution, metabolism, excretion, and toxicology (ADME/Tox). With the recent rebirth of AI related to pharma, it is timely to present this collaborative commentary to capture the diverging opinions on the past, present and future role of AI for ADME/Tox and how it can be applied in newer areas such as nanomaterials.
Topics: Algorithms; Artificial Intelligence; Computational Biology; Computer Simulation; Congresses as Topic; Decision Making; Deep Learning; Drug Design; Drug Discovery; Humans; Machine Learning; Mitochondria; Pharmacokinetics; Technology, Pharmaceutical
PubMed: 31000801
DOI: 10.1038/s41563-019-0332-5 -
Molecules (Basel, Switzerland) Dec 2022Natural medicine has been widely used for clinical treatment and health care in many countries and regions. Additionally, extracting active ingredients from traditional... (Review)
Review
Natural medicine has been widely used for clinical treatment and health care in many countries and regions. Additionally, extracting active ingredients from traditional Chinese medicine and other natural plants, defining their chemical structure and pharmacological effects, and screening potential druggable candidates are also uprising directions in new drug research and development. Physiologically based pharmacokinetic (PBPK) modeling is a mathematical modeling technique that simulates the absorption, distribution, metabolism, and elimination of drugs in various tissues and organs in vivo based on physiological and anatomical characteristics and physicochemical properties. PBPK modeling in drug research and development has gradually been recognized by regulatory authorities in recent years, including the U.S. Food and Drug Administration. This review summarizes the general situation and shortcomings of the current research on the pharmacokinetics of natural medicine and introduces the concept and the advantages of the PBPK model in the study of pharmacokinetics of natural medicine. Finally, the pharmacokinetic studies of natural medicine using the PBPK models are summed up, followed by discussions on the applications of PBPK modeling to the enzyme-mediated pharmacokinetic changes, special populations, new drug research and development, and new indication adding for natural medicine. This paper aims to provide a novel strategy for the preclinical research and clinical use of natural medicine.
Topics: Pharmaceutical Preparations; Medicine; Models, Biological; Pharmacokinetics
PubMed: 36557804
DOI: 10.3390/molecules27248670