Interindividual variability in CYP3A-mediated venetoclax metabolism in vitro and in vivo in patients with chronic lymphocytic leukemia.

Venetoclax is a first-in-class orally administered B-cell lymphoma-2 inhibitor used to treat chronic lymphocytic leukemia (CLL). Venetoclax is primarily metabolized in the liver by cytochrome P450 (CYP) 3A4 to its major metabolite M27, via M5, and M2, M3, and M4 via oxidation. Although venetoclax is a breakthrough in CLL treatment, managing drug safety and toxicity remains a clinical challenge.

CBD and THC in Special Populations: Pharmacokinetics and Drug-Drug Interactions.

Cannabinoid use has surged in the past decade, with a growing interest in expanding cannabidiol (CBD) and delta-9-tetrahydrocannabinol (THC) applications into special populations. Consequently, the increased use of CBD and THC raises the risk of drug-drug interactions (DDIs). Nevertheless, DDIs for cannabinoids, especially in special populations, remain inadequately investigated.

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.

Advances and Challenges in Modeling Cannabidiol Pharmacokinetics and Hepatotoxicity.

Cannabidiol (CBD) is a pharmacologically active metabolite of cannabis that is US Food and Drug Administration approved to treat seizures associated with Lennox-Gastaut syndrome, Dravet syndrome, and tuberous sclerosis complex in children aged 1 year and older. During clinical trials, CBD caused dose-dependent hepatocellular toxicity at therapeutic doses. The risk for toxicity was increased in patients taking valproate, another hepatotoxic antiepileptic drug, through an unknown mechanism.

A Review of CYP-Mediated Drug Interactions: Mechanisms and In Vitro Drug-Drug Interaction Assessment.

Drug metabolism is a major determinant of drug concentrations in the body. Drug-drug interactions (DDIs) caused by the co-administration of multiple drugs can lead to alteration in the exposure of the victim drug, raising safety or effectiveness concerns. Assessment of the DDI potential starts with in vitro experiments to determine kinetic parameters and identify risks associated with the use of comedication that can inform future clinical studies.

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.

Cytosolic Enzymes Generate Cannabinoid Metabolites 7-Carboxycannabidiol and 11-Nor-9-carboxytetrahydrocannabinol.

The cannabinoids cannabidiol (CBD) and delta-9-tetrahydrocannabinol (THC) undergo extensive oxidative metabolism in the liver. Although cytochromes P450 form the primary, pharmacologically active, hydroxylated metabolites of CBD and THC, less is known about the enzymes that generate the major circulating metabolites of CBD and THC, 7-carboxy-CBD and 11-carboxy-THC, respectively. The purpose of this study was to elucidate the enzymes involved in forming these metabolites.

Verifying in vitro-determined enzyme contributions to cannabidiol clearance for exposure predictions in human through physiologically-based pharmacokinetic modeling.

Cannabidiol (CBD) is approved for treatment of seizures associated with two forms of epilepsy that become apparent in infancy or early childhood. To consider an adult physiologically-based pharmacokinetic (PBPK) model for pediatric scaling, we assessed in vitro-derived cytochrome P450 (CYP) and uridine 5'-diphospho-glucuronosyltransferase (UGT) enzyme contributions to CBD clearance in human. An i.

Vaping additives cannabinoid oil and vitamin E acetate adhere to and damage the human airway epithelium.

E-cigarette, or vaping product use-associated lung injury (EVALI), is a severe respiratory disorder that caused a sudden outbreak of hospitalized young people in 2019. Using cannabis oil containing vaping products, including vitamin E acetate contaminants, was found to be strongly associated with EVALI. However, the underlying tissue impacts of the condition are still largely unknown.

Interindividual Variability in Cytochrome P450 3A and 1A Activity Influences Sunitinib Metabolism and Bioactivation.

Sunitinib is an orally administered tyrosine kinase inhibitor associated with idiosyncratic hepatotoxicity; however, the mechanisms of this toxicity remain unclear. We have previously shown that cytochromes P450 1A2 and 3A4 catalyze sunitinib metabolic activation via oxidative defluorination leading to a chemically reactive, potentially toxic quinoneimine, trapped as a glutathione (GSH) conjugate (M5). The goals of this study were to determine the impact of interindividual variability in P450 1A and 3A activity on sunitinib bioactivation to the reactive quinoneimine and sunitinib -dealkylation to the primary active metabolite -desethylsunitinib (M1).

Cytochrome P450-Catalyzed Metabolism of Cannabidiol to the Active Metabolite 7-Hydroxy-Cannabidiol.

Cannabidiol (CBD) is a naturally occurring nonpsychotoxic phytocannabinoid that has gained increasing attention as a popular consumer product and for its use in Food and Drug Administration-approved Epidiolex (CBD oral solution) for the treatment of Lennox-Gastaut syndrome and Dravet syndrome. CBD was previously reported to be metabolized primarily by CYP2C19 and CYP3A4, with minor contributions from UDP-glucuronosyltransferases. 7-Hydroxy-CBD (7-OH-CBD) is the primary active metabolite with equipotent activity compared with CBD.

Case Study 11: Considerations for Enzyme Mapping Experiments-Interaction Between the Aldehyde Oxidase Inhibitor Hydralazine and Glutathione.

Often it may be convenient and efficient to address multiple research questions with a single experiment. In many instances, however, the best approach is to design the experiment to address one question at a time. The design of enzyme mapping experiments is discussed in this chapter, focusing on considerations pertinent to the study of aldehyde oxidase (AO) vs.