Evaluating cannabidiol-induced liver injury with and without valproate using a three-dimensional human hepatocyte spheroid model.

Cannabidiol (CBD) and valproate (VPA) are anti-epileptic medications commonly co-prescribed to treat seizures due to Lennox-Gastaut syndrome, Dravet syndrome, and tuberous sclerosis complex in children. Clinical trial data have demonstrated that CBD carries a risk for severe hepatotoxicity that is greatly increased when prescribed with VPA through an unknown mechanism. The aim of this study was to investigate CBD-induced liver injury in combination with VPA using an in vitro liver model.

Elucidating Molecular Mechanisms of Drug-Induced Hepatotoxicity of Lapatinib.

DILI (drug-induced liver injury) remains a critical liability in drug discovery and development. However, there are few in vitro and preclinical models to predict DILI, and the knowledge of DILI molecular targets is even more limited. The lapatinib () prescription label carries a black box warning for idiosyncratic hepatotoxicity and this has prompted numerous studies aimed at understanding the underlying molecular mechanisms.

Wellness in the invisible workforce: a pilot well-being study in black, indigenous, and people of color (BIPOC) women faculty in the pharmacy and pharmaceutical sciences.

Background: Black, Indigenous, and other People of Color (BIPOC) women faculty are underrepresented in biomedical sciences and higher education. This disparity has been highlighted in previous studies to harm productivity, career progression, and well-being. This pilot study aimed to assess the perceived impact of a longitudinal well-being program for BIPOC women faculty, estimating its effects on well-being, burnout, and self-efficacy.

Impact of variation in CYP3A and CYP2C8 on tucatinib metabolic clearance in human liver microsomes.

Tucatinib is a small molecule tyrosine kinase inhibitor indicated for HER2-positive breast cancer. This recently approved drug is primarily metabolized by cytochrome P450 (P450) 2C8 and CYP3A. Given the interindividual variability in the pharmacokinetics of some kinase inhibitors, the present study explored how variability in CYP2C8 and CYP3A activities and concentrations can influence variability in overall tucatinib metabolic clearance in vitro.

Impact of sex and pregnancy on hepatic CYP3A4 expression and activity in a humanized mouse model.

Cytochrome P450 (CYP) 3A4 is an essential drug-metabolizing enzyme in humans, which shows substantial interindividual variation in response to various intrinsic and extrinsic factors such as sex and pregnancy. In humans, higher CYP3A4 metabolism has been observed in females compared with that in males and in pregnant compared with that in nonpregnant individuals, which has been linked to increased CYP3A4 expression in liver. However, sex differences and pregnancy-mediated changes in hepatic CYP3A4 expression and activity in vivo are not fully understood.

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.

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).

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.

Biotransformation research advances - 2022 year in review.

This annual review is the eighth of its kind since 2016 (Baillie et al. 2016, Khojasteh et al. 2017, Khojasteh et al.

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.

Formation of CYP3A-specific metabolites of ibrutinib in vitro is correlated with hepatic CYP3A activity and 4β-hydroxycholesterol/cholesterol ratio.

Ibrutinib is an orally administered Bruton's tyrosine kinase inhibitor approved for the treatment of B-cell malignancies, including chronic lymphocytic leukemia. Ibrutinib is metabolized primarily via oxidation by cytochrome P450 (CYP) 3A4/5 to M37 (the primary active metabolite), M34, and M25. The objectives of this study were to assess the relationship between formation of the major CYP3A-specific ibrutinib metabolites in vitro and hepatic CYP3A activity and protein abundance, and to evaluate the utility of the endogenous CYP3A biomarker, plasma 4β-hydroxycholesterol (4β-HC) to cholesterol ratio, to predict ibrutinib metabolite formation in individual cadaveric donors with matching hepatocytes.

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.

Bioactivation and reactivity research advances - 2021 year in 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.

Biotransformation novel advances - 2021 year in review.

Biotransformation field is constantly evolving with new molecular structures and discoveries of metabolic pathways that impact efficacy and safety. Recent review by Kramlinger et al. (2022) nicely captures the future (and the past) of highly impactful science of biotransformation (see the first article).

Association of lipid profile biomarkers with breast cancer by molecular subtype: analysis of the MEND study.

There is conflicting evidence on the role of lipid biomarkers in breast cancer (BC), and no study to our knowledge has examined this association among African women. We estimated odds ratios (ORs) and 95% confidence intervals (95% CI) for the association of lipid biomarkers-total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL), and triglycerides-with odds of BC overall and by subtype (Luminal A, Luminal B, HER2-enriched and triple-negative or TNBC) for 296 newly diagnosed BC cases and 116 healthy controls in Nigeria. Each unit standard deviation (SD) increase in triglycerides was associated with 39% increased odds of BC in fully adjusted models (aOR: 1.

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.