WHO CAN USE YOUR CELLS OR TISSUES FOR SCIENTIFIC RESEARCH?

Informed consent is the process of obtaining permission from human participants to use their cells and tissues or otherwise include them in research studies. With informed consent, scientists can use human cells or tissues in experiments to learn more about the human body and to test new medicines. This article describes how these tissues are obtained, and the ethical concerns regarding the use of human tissues in research. The story of Henrietta Lacks and her immortal HeLa cell line is discussed, to demonstrate the importance of informed consent and to showcase Henrietta's valuable contributions to research and modern medicine.

Kinase Inhibitors FDA Approved 2018-2023: Drug Targets, Metabolic Pathways, and Drug-Induced Toxicities.

Small molecule kinase inhibitors are one of the fastest growing classes of drugs, which are approved by the US Food and Drug Administration (FDA) for cancer and noncancer indications. As of September 2023, there were over 70 FDA-approved small molecule kinase inhibitors on the market, 42 of which were approved in the past five years (2018-2023). This minireview discusses recent advances in our understanding of the pharmacology, metabolism, and toxicity profiles of recently approved kinase inhibitors with a central focus on tyrosine kinase inhibitors (TKIs). In this minireview we discuss the most common therapeutic indications and molecular target(s) of kinase inhibitors FDA approved 2018-2023. We also describe unique aspects of the metabolism, bioactivation, and drug-drug interaction (DDI) potential of kinase inhibitors; discuss drug toxicity concerns related to kinase inhibitors, such as drug-induced liver injury; and highlight clinical outcomes and challenges relevant to TKI therapy. Case examples are provided for common TKI targets, metabolism pathways, DDI potential, and risks for serious adverse drug reactions. The minireview concludes with a discussion of perspectives on future research to optimize TKI therapy to maximize efficacy and minimize drug toxicity. SIGNIFICANCE STATEMENT: This minireview highlights important aspects of the clinical pharmacology and toxicology of small molecule kinase inhibitors FDA approved 2018-2023. We describe key advances in the therapeutic indications and molecular targets of TKIs. The major metabolism pathways and toxicity profiles of recently approved TKIs are discussed. Clinically relevant case examples are provided that demonstrate the risk for hepatotoxic drug interactions involving TKIs and coadministered drugs.

Novel Approaches to Characterize Individual Drug Metabolism and Advance Precision Medicine.

Interindividual variability in drug metabolism can significantly affect drug concentrations in the body and subsequent drug response. Understanding an individual's drug metabolism capacity is important for predicting drug exposure and developing precision medicine strategies. The goal of precision medicine is to individualize drug treatment for patients to maximize efficacy and minimize drug toxicity. While advances in pharmacogenomics have improved our understanding of how genetic variations in drug-metabolizing enzymes (DMEs) affect drug response, nongenetic factors are also known to influence drug metabolism phenotypes. This minireview discusses approaches beyond pharmacogenetic testing to phenotype DMEs-particularly the cytochrome P450 enzymes-in clinical settings. Several phenotyping approaches have been proposed: traditional approaches include phenotyping with exogenous probe substrates and the use of endogenous biomarkers; newer approaches include evaluating circulating noncoding RNAs and liquid biopsy-derived markers relevant to DME expression and function. The goals of this minireview are to 1) provide a high-level overview of traditional and novel approaches to phenotype individual drug metabolism capacity, 2) describe how these approaches are being applied or can be applied to pharmacokinetic studies, and 3) discuss perspectives on future opportunities to advance precision medicine in diverse populations. SIGNIFICANCE STATEMENT: This minireview provides an overview of recent advances in approaches to characterize individual drug metabolism phenotypes in clinical settings. It highlights the integration of existing pharmacokinetic biomarkers with novel approaches; also discussed are current challenges and existing knowledge gaps. The article concludes with perspectives on the future deployment of a liquid biopsy-informed physiologically based pharmacokinetic strategy for patient characterization and precision dosing.

Cytochromes P450 2C8 and 3A Catalyze the Metabolic Activation of the Tyrosine Kinase Inhibitor Masitinib.

Masitinib is a small molecule tyrosine kinase inhibitor under investigation for the treatment of amyotrophic lateral sclerosis, mastocytosis, and COVID-19. Hepatotoxicity has been reported in some patients while taking masitinib. The liver injury is thought to involve hepatic metabolism of masitinib by cytochrome P450 (P450) enzymes to form chemically reactive, potentially toxic metabolites. The goal of the current investigation was to determine the P450 enzymes involved in the metabolic activation of masitinib in vitro. In initial studies, masitinib (30 µM) was incubated with pooled human liver microsomes in the presence of NADPH and potassium cyanide to trap reactive iminium ion metabolites as cyano adducts. Masitinib metabolites and cyano adducts were analyzed using reversed-phase liquid chromatography-tandem mass spectrometry. The primary active metabolite, N-desmethyl masitinib (M485), and several oxygenated metabolites were detected along with four reactive metabolite cyano adducts (MCN510, MCN524, MCN526, and MCN538). To determine which P450 enzymes were involved in metabolite formation, reaction phenotyping experiments were conducted by incubation of masitinib (2 µM) with a panel of recombinant human P450 enzymes and by incubation of masitinib with human liver microsomes in the presence of P450-selective chemical inhibitors. In addition, enzyme kinetic assays were conducted to determine the relative kinetic parameters (apparent Km and Vmax) of masitinib metabolism and cyano adduct formation. Integrated analysis of the results from these experiments indicates that masitinib metabolic activation is catalyzed primarily by P450 3A4 and 2C8, with minor contributions from P450 3A5 and 2D6. These findings provide further insight into the pathways involved in the generation of reactive, potentially toxic metabolites of masitinib. Future studies are needed to evaluate the impact of masitinib metabolism on the toxicity of the drug in vivo.