.

Several clinical studies have shown that COVID-19 increases the systemic concentration of drugs in hospitalized COVID-19 patients. However, it is unclear how COVID-19-mediated bidirectional dysregulation of hepatic and pulmonary CYP3A4 impacts drug concentrations, especially in the lung tissue which is most affected by the disease. Herein, PBPK modeling was used to demonstrate the differences in systemic and pulmonary concentrations of four respiratory infectious disease drugs when CYP3A4 is concurrently downregulated in the liver and upregulated in the lung based on existing clinical data on COVID-19 - CYP3A4 interactions at varying severity levels including outpatients, non-ICU, and ICU patients.

Healthcare provider and patient perspectives on the implementation of pharmacogenetic-guided treatment in routine clinical practice.

Objective: This study aims to understand patient and healthcare provider perspectives on the integration and application of pharmacogenetics (PGx) testing in routine clinical practice.

Methods: Two anonymous online surveys were distributed globally for healthcare providers and patients respectively on the Qualtrics platform (version 3.24).

COVID-19 severity gradient differentially dysregulates clinically relevant drug processing genes in nasopharyngeal swab samples.

Aim: Understanding how COVID-19 impacts the expression of clinically relevant drug metabolizing enzymes and membrane transporters (DMETs) is vital for addressing potential safety and efficacy concerns related to systemic and peripheral drug concentrations. This study investigates the impact of COVID-19 severity on DMETs expression and the underlying mechanisms to inform the design of precise clinical dosing regimens for affected patients.

Methods: Transcriptomics analysis of 102 DMETs, 10 inflammatory markers, and 12 xenosensing regulatory genes was conducted on nasopharyngeal swabs from 50 SARS-CoV-2 positive (17 outpatients, 16 non-ICU, and 17 ICU) and 13 SARS-CoV-2 negative individuals, clinically tested through qPCR, in the Greater Toronto area from October 2020 to October 2021.

SARS-CoV-2 infection dysregulates the expression of clinically relevant drug metabolizing enzymes in Vero E6 cells and membrane transporters in human lung tissues.

SARS-CoV-2-mediated interactions with drug metabolizing enzymes and membrane transporters (DMETs) in different tissues, especially lung, the main affected organ may limit the clinical efficacy and safety profile of promising COVID-19 drugs. Herein, we investigated whether SARS-CoV-2 infection could dysregulate the expression of 25 clinically relevant DMETs in Vero E6 cells and postmortem lung tissues from COVID-19 patients. Also, we assessed the role of 2 inflammatory and 4 regulatory proteins in modulating the dysregulation of DMETs in human lung tissues.

Pharmacokinetic considerations to optimize clinical outcomes for COVID-19 drugs.

The development of clinically effective drugs that could complement existing vaccines is urgently needed to reduce the morbidity and mortality associated with COVID-19. Drug-metabolizing enzymes, membrane-associated drug transporters, and inflammatory responses can partly determine the safety and efficacy of COVID-19 drugs by controlling their concentrations in both the systemic circulation and in peripheral tissues. It is still unknown how these factors affect how well COVID-19 drugs work in the clinic.

An HPLC-UV validated bioanalytical method for measurement of phase 1 kinetics of α-synuclein binding bifunctional compounds.

Aggregates of the protein α-synuclein are associated with pathophysiology of Parkinson's disease and are present in Lewy Bodies found in the brains of Parkinson's patients. We previously demonstrated that bifunctional compounds composed of caffeine linked via a six carbon chain to either 1-aminoindan (C-6-I) or nicotine (C-6-N) bind α-synuclein and protect yeast cells from α-synuclein mediated toxicity.A critical step in development of positron emission tomography (PET) probes for neurodegenerative diseases is evaluation of their metabolic stability.

Potential application of mass spectrometry imaging in pharmacokinetic studies.

Although liquid chromatography-tandem mass spectrometry is the gold standard analytical platform for the quantification of drugs, metabolites, and biomarkers in biological samples, it cannot localise them in target tissues.The localisation and quantification of drugs and/or their associated metabolites in target tissues is a more direct measure of local drug exposure, biodistribution, efficacy, and regional toxicity compared to the traditional substitute studies using plasma.Therefore, combining high spatial resolution imaging functionality with the superior selectivity and sensitivity of mass spectrometry into one analytical technique will be a valuable tool for targeted localisation and quantification of drugs, metabolites, and biomarkers in tissues.

Diagnostic and therapeutic agents that target alpha-synuclein in Parkinson's disease.

The development of disease-modifying drugs and differential diagnostic agents is an urgent medical need in Parkinson's disease. Despite the complex pathophysiological pathway, the misfolding of alpha-synuclein has been identified as a putative biomarker for detecting the onset and progression of the neurodegeneration associated with Parkinson's disease. Identifying the most appropriate alpha-synuclein-based diagnostic modality with clinical translation will revolutionize the diagnosis of Parkinson's.

Relevance of ABC Transporters in Drug Development.

ATP-binding cassette (ABC) transporters play a critical role in protecting vital organs such as the brain and placenta against xenobiotics, as well as in modulating the pharmacological and toxicological profile of several drug candidates by restricting their penetration through cellular and tissue barriers. This review paper describes the structure and function of ABC transporters as well as the role of P-glycoprotein, multidrug resistance-associated protein 2 and breast cancer resistance protein in the disposition of drugs. Furthermore, a review of the in vitro and in vivo techniques for evaluating the interaction between drugs and ABC transporters is provided.

Bioanalytical strategies in drug discovery and development.

A reliable, rapid, and effective bioanalytical method is essential for the determination of the pharmacokinetic, pharmacodynamic, and toxicokinetic parameters that inform the safety and efficacy profile of investigational drugs. The overall goal of bioanalytical method development is to elucidate the procedure and operating conditions under which a method can sufficiently extract, qualify, and/or quantify the analyte(s) of interest and/or their metabolites for the intended purpose. Given the difference in the physicochemical properties of small and large molecule drugs, different strategies need to be adopted for the development of an effective and efficient bioanalytical method.

Employing metabolism to guide design of F-labelled PET probes of novel α-synuclein binding bifunctional compounds.

A challenge in the development of novel F-labelled positron emission tomography (PET) imaging probes is identification of metabolically stable sites to incorporate the F radioisotope. Metabolic loss of F from PET probes can lead to misleading biodistribution data as displaced F can accumulate in various tissues.In this study we report on hepatic microsomal metabolism of novel caffeine containing bifunctional compounds (C-6-I, C-6-N, C-6-C) that can prevent aggregation of α-synuclein, which is associated with the pathophysiology of Parkinson's disease.

Introduction to the mini special issue on next generation drug discovery and development: rethinking translational pharmacology for accelerated drug development.

The coronavirus disease (COVID-19) pandemic further revealed the barriers to accelerated discovery and development of transformative medicines for life threatening diseases. To effectively and efficiently respond to unmet medical needs, efforts should be directed towards revolutionizing the predictive capability of non-clinical surrogates that inform drug discovery and development programs. I developed this mini special issue amidst the COVID-19 pandemic to evaluate recent advancements and opportunities for four main subthemes that support drug discovery and development including prediction of metabolic pathways, translational pharmacokinetic and pharmacodynamic studies, pharmacogenomics, and trends in bioanalysis.

Pharmacogenomics in the era of next generation sequencing - from byte to bedside.

Pharmacogenetic research has resulted in the identification of a multitude of genetic variants that impact drug response or toxicity. These polymorphisms are mostly common and have been included as actionable information in the labels of numerous drugs. In addition to common variants, recent advances in Next Generation Sequencing (NGS) technologies have resulted in the identification of a plethora of rare and population-specific pharmacogenetic variations with unclear functional consequences that are not accessible by conventional forward genetics strategies.

Advances in the study of drug metabolism - symposium report of the 12th Meeting of the International Society for the Study of Xenobiotics (ISSX).

The 12th International Society for the Study of Xenobiotics (ISSX) meeting, held in Portland, OR, USA from July 28 to 31, 2019, was attended by diverse members of the pharmaceutical sciences community. The ISSX New Investigators Group provides learning and professional growth opportunities for student and early career members of ISSX. To share meeting content with those who were unable to attend, the ISSX New Investigators herein elected to highlight the "" symposium, as it engaged attendees with diverse backgrounds.

Tandem mass spectrometric analysis of novel caffeine scaffold-based bifunctional compounds for Parkinson's disease.

Rationale: Novel bifunctional compounds composed of a caffeine scaffold attached to nicotine (C -6-N), 1-aminoindan (C -6-I), or caffeine (C -6-C ) were designed as therapeutics or diagnostics for Parkinson's disease (PD). In order to probe their pharmacological and toxicological profile, an appropriate analytical method is required. The goal of this study is to establish a tandem mass spectrometric fingerprint for the development of quantitative and qualitative methods that will aid future assessment of the in vitro and in vivo absorption, distribution, metabolism, excretion (ADME) and pharmacokinetic properties of these lead bifunctional compounds for PD.