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International Journal of Molecular... Jan 2023RNA-mediated drugs are a rapidly growing class of therapeutics. Over the last five years, the list of FDA-approved RNA therapeutics has expanded owing to their unique... (Review)
Review
RNA-mediated drugs are a rapidly growing class of therapeutics. Over the last five years, the list of FDA-approved RNA therapeutics has expanded owing to their unique targets and prolonged pharmacological effects. Their absorption, distribution, metabolism, and excretion (ADME) have important clinical im-plications, but their pharmacokinetic properties have not been fully understood. Most RNA therapeutics have structural modifications to prevent rapid elimination from the plasma and are administered intravenously or subcutaneously, with some exceptions, for effective distribution to target organs. Distribution of drugs into tissues depends on the addition of a moiety that can be transported to the target and RNA therapeutics show a low volume of distribution because of their molecular size and negatively-charged backbone. Nucleases metabolize RNA therapeutics to a shortened chain, but their metabolic ratio is relatively low. Therefore, most RNA therapeutics are excreted in their intact form. This review covers not only ADME features but also clinical pharmacology data of the RNA therapeutics such as drug-drug interaction or population pharmacokinetic analyses. As the market of RNA therapeutics is expected to rapidly expand, comprehensive knowledge will contribute to interpreting and evaluating the pharmacological properties.
Topics: Drug Interactions; Chemical Phenomena; Biological Transport; Pharmacokinetics
PubMed: 36614189
DOI: 10.3390/ijms24010746 -
American Journal of Perinatology Jul 2019Neonates are a uniquely vulnerable population, compromised by immature physiology and critical illness if born premature. Furthermore, neonates have frequent exposures... (Review)
Review
Neonates are a uniquely vulnerable population, compromised by immature physiology and critical illness if born premature. Furthermore, neonates have frequent exposures to drugs that lack adequate data on safety, efficacy, and appropriate dosing in this population. Key physiologic differences between neonates and older children and adults affect drug absorption, distribution, metabolism, and elimination. Adequate understanding and consideration of these differences is essential to ensure optimal dosing of therapeutic agents in this vulnerable population. Moreover, direct study of neonates through appropriately designed pharmacokinetic and pharmacodynamic studies can ensure the development of safe and effective therapeutics in our youngest populations of patients.
Topics: Absorption, Physiological; Humans; Infant, Newborn; Pharmaceutical Preparations; Pharmacokinetics; Tissue Distribution
PubMed: 31238353
DOI: 10.1055/s-0039-1691772 -
Seminars in Perinatology Apr 2020The effects of the many biochemical and physiologic changes of pregnancy on the dose-response relationship of drugs administered to pregnant women are poorly understood.... (Review)
Review
The effects of the many biochemical and physiologic changes of pregnancy on the dose-response relationship of drugs administered to pregnant women are poorly understood. The dose-response relationship is affected by pharmacokinetics, or what the body does to a drug, and pharmacodynamics, or what a drug does to the body. Insights into the potential effects of the changes of pregnancy on one aspect of the dose-response relationship of a drug can be obtained by studying the pharmacokinetics of the drug in the various stages of pregnancy and the postpartum period. There are several available approaches to studying pharmacokinetic changes in pregnancy. Single trough screening studies can provide qualitative estimates of elimination clearance, which with the dosing rate determines the steady-state drug concentration, throughout pregnancy and into the postpartum period. Population pharmacokinetic studies such as two stage pharmacokinetic studies and studies using a nonlinear mixed effects pharmacokinetic modeling approach can characterize pharmacokinetic changes more rigorously.
Topics: Absorption, Physiological; Dose-Response Relationship, Drug; Drug Elimination Routes; Female; Humans; Pharmaceutical Preparations; Pharmacokinetics; Pharmacological Phenomena; Pregnancy; Tissue Distribution
PubMed: 32093881
DOI: 10.1016/j.semperi.2020.151227 -
Drug Delivery Dec 2019As an emerging novel drug carrier, nanoparticles provide a promising way for effective treatment of parasitic diseases by overcoming the shortcomings of low... (Review)
Review
As an emerging novel drug carrier, nanoparticles provide a promising way for effective treatment of parasitic diseases by overcoming the shortcomings of low bioavailability, poor cellular permeability, nonspecific distribution and rapid elimination of antiparasitic drugs from the body. In recent years, some kinds of ideal nanocarriers have been developed for antiparasitic drug delivery. In this review, the progress of the enhanced antiparasitic effects of different nanoparticles payload and their influencing factors were firstly summarized. Secondly, the transport and disposition process in the body were reviewed. Finally, the challenges and prospects of nanoparticles for antiparasitic drug delivery were proposed. This review will help scholars to understand the development trend of nanoparticles in the treatment of parasitic diseases and explore strategies in the development of more efficient nanocarriers to overcome the difficulty in the treatment of parasite infections in the future.
Topics: Animals; Antiparasitic Agents; Drug Carriers; Drug Liberation; Humans; Liposomes; Nanoparticles; Particle Size; Surface Properties; Tissue Distribution
PubMed: 31746243
DOI: 10.1080/10717544.2019.1692968 -
Environment International May 2022Arsenic exists universally in freshwater and marine environments, threatening the survival of aquatic organisms and human health. To elucidate arsenic bioaccumulation... (Review)
Review
Arsenic exists universally in freshwater and marine environments, threatening the survival of aquatic organisms and human health. To elucidate arsenic bioaccumulation and biotransformation processes in aquatic organisms, this review evaluates the dissolved uptake, dietary assimilation, biotransformation, and elimination of arsenic in aquatic organisms and discusses the major factors influencing these processes. Environmental factors such as phosphorus concentration, pH, salinity, and dissolved organic matter influence arsenic absorption from aquatic systems, whereas ingestion rate, gut passage time, and gut environment affect the assimilation of arsenic from foodstuffs. Arsenic bioaccumulation and biotransformation mechanisms differ depending on specific arsenic species and the involved aquatic organism. Although some enzymes engaged in arsenic biotransformation are known, deciphering the complicated synthesis and degradation pathway of arsenobetaine remains a challenge. The elimination of arsenic involves many processes, such as fecal excretion, renal elimination, molting, and reproductive processes. This review facilitates our understanding of the environmental behavior and biological fate of arsenic and contributes to regulation of the environmental risk posed by arsenic pollution.
Topics: Aquatic Organisms; Arsenic; Bioaccumulation; Biotransformation; Humans; Water Pollutants, Chemical
PubMed: 35378441
DOI: 10.1016/j.envint.2022.107221 -
British Journal of Clinical Pharmacology Dec 2022The population pharmacokinetics of amiodarone and its active metabolite, N-desethylamiodarone (DEA) were investigated in paediatric patients with arrhythmias, mainly...
The population pharmacokinetics of amiodarone and its active metabolite, N-desethylamiodarone (DEA) were investigated in paediatric patients with arrhythmias, mainly supraventricular tachycardias. A total of 55 patients from the Department of Pediatric Intensive Care and Pediatric Cardiology at Necker-Enfants malades Hospital (Paris, France) provided 72 concentrations for both amiodarone and DEA following repeated oral or intravenous administration. Blood samples drawn for biological analyses were used for drug concentrations. Plasma amiodarone concentrations were measured by a liquid chromatography method coupled with mass spectrometry and the data were modelled using the software Monolix 2019R2. Parent pharmacokinetics was described with a 2-compartment open model and the metabolite formation was connected to the central parent compartment. Parameter estimates scaled allometrically on bodyweight (normalized to 70 kg) were, respectively (% relative standard errors, RSEs), 6.32 (31%) and 7.14 L/h (26%) for elimination (CL) and intercompartmental clearances and 167 (31%) and 3930 (32%) L for V and V . Oral bioavailability was 0.362 (21.5%). The clearance between subject variability (ω, square root of the variance) was 0.462 (RSE 21%). The proportional residual variabilities were respectively 0.453 (RSE 13%) and 0.423 (RSE 12%) for amiodarone and DEA respectively. The terminal half-lives were 34 and 14.5 days for amiodarone and DEA, respectively. A dosage schedule was established for 3 weight bands in 2 time periods. The high pharmacokinetic variability suggests that therapeutic drug monitoring might be useful to improve individual efficacy and safety.
Topics: Humans; Child; Administration, Oral; Amiodarone; Biological Availability; Chromatography, Liquid
PubMed: 35816412
DOI: 10.1111/bcp.15458 -
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 -
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 -
Drug Metabolism Reviews Aug 2022This year's review on bioactivation and reactivity began as a part of the annual review on biotransformation and bioactivation led by Cyrus Khojasteh (see references).... (Review)
Review
This year's review on bioactivation and reactivity began as a part of the annual review on biotransformation and bioactivation led by Cyrus Khojasteh (see references). Increased contributions from experts in the field led to the development of a stand alone edition for the first time this year focused specifically on bioactivation and reactivity. Our objective for this review is to highlight and share articles which we deem influential and significant regarding the development of covalent inhibitors, mechanisms of reactive metabolite formation, enzyme inactivation, and drug safety. Based on the selected articles, we created two sections: (1) reactivity and enzyme inactivation, and (2) bioactivation mechanisms and safety (Table 1). Several biotransformation experts have contributed to this effort from academic and industry settings.[Table: see text].
Topics: Biotransformation; Humans; Microsomes, Liver
PubMed: 35876116
DOI: 10.1080/03602532.2022.2097254 -
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