A Pharmacokinetic/Toxicodynamic Model of Cisplatin Nephrotoxicity Using the Kidney Injury Molecule-1 Biomarker.

Cisplatin is a platinum-based chemotherapeutic that causes acute kidney injury in over 30% of patients. The aim of this study was to develop a population pharmacokinetic/toxicodynamic (PKTD) model of cisplatin-induced kidney injury that incorporated plasma total platinum and urinary kidney injury molecule-1 (KIM-1) concentrations. Cancer patients receiving their first or second round of cisplatin-containing chemotherapy (n=39) were prospectively randomized to a 5-HT antagonist (5-HTA) antiemetic (ondansetron, granisetron, or palonosetron) and had blood and urine collected over 10 days.

Population Pharmacokinetic Model of Platinum Disposition in Cancer Patients Receiving Cisplatin and Randomized to 5-HT Antagonist Antiemetic Drugs.

Cisplatin is a platinum-based chemotherapeutic drug used to treat many types of cancer. The aim of this study was to develop a population pharmacokinetic model that incorporates plasma unbound and bound platinum levels. Cancer patients undergoing their first or second cycle of cisplatin-containing chemotherapy (n = 33) were prospectively randomized to receive a 5-hydroxytryptamine (5-HT) antagonist (5-HTA) antiemetic (ondansetron, granisetron, or palonosetron) followed by blood collection over 10 days.

Nonalcoholic steatohepatitis increases plasma retention of sorafenib-glucuronide in a mouse model by altering hepatocyte hopping.

Hepatocyte hopping is the hepatocyte-to-sinusoid-to-hepatocyte shuttling that increases the efficiency of hepatic elimination of xenobiotics. This phenomenon is mediated efflux of hepatic metabolites by Mrp3 and reuptake by Oatp transporters in sequential hepatocytes until eventual biliary efflux by Mrp2. Sorafenib-glucuronide (SFB-G), the major metabolite of sorafenib (SFB), undergoes hepatocyte hopping, leading to efficient biliary elimination.

Sociodemographic and dietary predictors of maternal and placental mycoestrogen concentrations in a US pregnancy cohort.

Background: Zearalenone (ZEN) is a mycotoxin contaminating grains and processed foods. ZEN alters nuclear estrogen receptor α/β signaling earning its designation as a mycoestrogen. Experimental evidence demonstrates that mycoestrogen exposure during pregnancy is associated with altered maternal sex steroid hormones, changes in placental size, and decreases in fetal weight and length.

Effects of therapeutically approved individual bile acids on the development of metabolic dysfunction-associated steatohepatitis a low bile acid mouse model.

Bile acid (BA) signaling dysregulation is an important etiology for the development of metabolic dysfunction-associated steatotic liver disease (MASLD). As diverse signaling molecules synthesized in the liver by pathways initiated with CYP7A1 and CYP27A1, BAs are endogenous modulators of farnesoid x receptor (FXR). FXR activation is crucial in maintaining BA homeostasis, regulating lipid metabolism, and suppressing inflammation.

Repurposing FDA-approved drugs to treat chemical weapon toxicities: Interactive case studies for trainees.

The risk of a terrorist attack in the United States has created challenges on how to effectively treat toxicities that result from exposure to chemical weapons. To address this concern, the United States has organized a trans-agency initiative across academia, government, and industry to identify drugs to treat tissue injury resulting from exposure to chemical threat agents. We sought to develop and evaluate an interactive educational session that provides hands-on instruction on how to repurpose FDA-approved drugs as therapeutics to treat toxicity from exposure to chemical weapons.

Determination of unbound platinum concentrations in human plasma using ultrafiltration and precipitation methods.

Quantification of the unbound portion of platinum (Pt) in human plasma is important for assessing the pharmacokinetics of the chemotherapeutic drug cisplatin. In this study, we sought to compare the recovery of unbound Pt using Nanosep® filters to 1) traditional filters (Centrifree®, Centrisart®, Amicon®) or trichloroacetic acid (TCA) protein precipitation, and 2) unbound, bound, and total Pt concentrations in clinical specimens. For the tested filters, the impact of 1) molecular weight cut-offs, 2) centrifugation force, and 3) total Pt concentration on Pt binding in human plasma was evaluated.

Associations between mycoestrogen exposure and sex steroid hormone concentrations in maternal serum and cord blood in the UPSIDE pregnancy cohort.

Zearalenone (ZEN) is a fungal-derived toxin found in global food supplies including cereal grains and processed foods, impacting populations worldwide through diet. Because the chemical structure of ZEN and metabolites closely resembles 17β-estradiol (E2), they interact with estrogen receptors α/β earning their designation as 'mycoestrogens'. In animal models, gestational exposure to mycoestrogens disrupts estrogen activity and impairs fetal growth.

Evaluation of Cisplatin-Induced Acute Kidney Injury in Patients Coprescribed Serotonin Receptor Antagonists: A Retrospective Analysis.

Key Points: Serotonin receptor antagonists reduce the incidence of AKI in patients receiving cisplatin as chemotherapy. New-generation serotonin receptors do not offer any additional advantage in terms of protection from cisplatin induced AKI.

Background: Cisplatin is an effective first-line therapy for a variety of cancers.

Hybrid non-animal modeling: A mechanistic approach to predict chemical hepatotoxicity.

Developing mechanistic non-animal testing methods based on the adverse outcome pathway (AOP) framework must incorporate molecular and cellular key events associated with target toxicity. Using data from an in vitro assay and chemical structures, we aimed to create a hybrid model to predict hepatotoxicants. We first curated a reference dataset of 869 compounds for hepatotoxicity modeling.

Membrane transporters in drug development and as determinants of precision medicine.

The effect of membrane transporters on drug disposition, efficacy and safety is now well recognized. Since the initial publication from the International Transporter Consortium, significant progress has been made in understanding the roles and functions of transporters, as well as in the development of tools and models to assess and predict transporter-mediated activity, toxicity and drug-drug interactions (DDIs). Notable advances include an increased understanding of the effects of intrinsic and extrinsic factors on transporter activity, the application of physiologically based pharmacokinetic modelling in predicting transporter-mediated drug disposition, the identification of endogenous biomarkers to assess transporter-mediated DDIs and the determination of the cryogenic electron microscopy structures of SLC and ABC transporters.

Fetoplacental Disposition and Toxicity of Cadmium in Mice Lacking the Bcrp Transporter.

The environmental toxicant cadmium (Cd) impairs the growth of rodents and humans in utero which in turn heightens susceptibility to diseases later in life. We previously demonstrated that the maternal-facing efflux transporter, breast cancer resistance protein (human BCRP/ABCG2, mouse Bcrp/Abcg2) confers resistance against Cd toxicity in human trophoblasts. In the current study, we sought to determine whether the absence of Bcrp alters the fetoplacental disposition and toxicity of Cd in mice.

Placental BCRP transporter reduces cadmium accumulation and toxicity in immortalized human trophoblasts.

Cadmium (Cd) is a ubiquitous environmental metal detectable in most pregnant women. Animal and human studies demonstrate that in utero exposure to Cd reduces birth weight and impairs perinatal growth due to placental toxicity. BCRP is a prominent transporter that can efflux xenobiotics from the placenta.

Integrating Concentration-Dependent Toxicity Data and Toxicokinetics To Inform Hepatotoxicity Response Pathways.

Failure of animal models to predict hepatotoxicity in humans has created a push to develop biological pathway-based alternatives, such as those that use in vitro assays. Public screening programs (e.g.

Cadmium reduces growth of male fetuses by impairing development of the placental vasculature and reducing expression of nutrient transporters.

In utero exposure to the toxic metal cadmium (Cd) alters fetoplacental growth in rodents and has been inversely associated with birth weight and infant size in some birth cohorts. Moreover, studies suggest that Cd may have differential effects on growth and development according to offspring sex. The purpose of the current study was to evaluate changes in male and female fetoplacental development following a single injection of saline (5 ml/kg ip) or cadmium chloride (CdCl, 2.

Optimized extraction and analysis methods using liquid chromatography-tandem mass spectrometry for zearalenone and metabolites in human placental tissue.

Zearalenone and its metabolites, a group of endocrine disrupting mycotoxins, have been linked to adverse reproductive health effects. They cross the placental barrier, potentially reaching the fetus. In this study, we adapted and optimized our protocol previously used for urine, to measure these mycotoxins in human placentas.

Engaging Students in Pharmacogenetics: Patient Case Studies Using the PharmGKB Website.

Cytochrome P450 (CYP) enzymes are important regulators of drug efficacy and toxicity. Genetic variation in isoforms can impact how well patients respond to medications or experience unwanted toxicities. PharmGKB is an online pharmacogenomics resource that collates the latest data and clinical guidelines on genetic variation and drug responses.

Gadolinium during human pregnancy following administration of gadolinium chelate before pregnancy.

Gadolinium (Gd), a toxic rare earth element, has been shown to dissociate from chelating agents and bioaccumulate within tissues, raising concerns about the possibility of their remobilization during pregnancy with subsequent free Gd exposures to developing fetuses. Gd chelates are among the most commonly used magnetic resonance imaging (MRI) contrast agents. This investigation was undertaken after the detection of elevated Gd (800-1000× higher than the usual rare earth element levels) in preliminary unpublished studies from the placentae of subjects in the NIH ECHO/UPSIDE Rochester Cohort Study and unpublished studies from placentae analyzed in formalin-fixed placental specimens from Surgical Pathology at the University of Rochester.

Data-Driven Quantitative Structure-Activity Relationship Modeling for Human Carcinogenicity by Chronic Oral Exposure.

Traditional methodologies for assessing chemical toxicity are expensive and time-consuming. Computational modeling approaches have emerged as low-cost alternatives, especially those used to develop quantitative structure-activity relationship (QSAR) models. However, conventional QSAR models have limited training data, leading to low predictivity for new compounds.

Protective role of the placental efflux transporter BCRP/ABCG2 in the relationship between prenatal cadmium exposure, placenta weight, and size at birth.

Background And Aim: Placental efflux transporter proteins, such as BCRP, reduce the placental and fetal toxicity of environmental contaminants but have received little attention in perinatal environmental epidemiology. Here, we evaluate the potential protective role of BCRP following prenatal exposure to cadmium, a metal that preferentially accumulates in the placenta and adversely impacts fetal growth. We hypothesized that individuals with a reduced function polymorphism in ABCG2, the gene encoding BCRP, would be most vulnerable to the adverse impacts of prenatal cadmium exposure, notably, smaller placental and fetal size.

High-throughput screening of toxicants that modulate extravillous trophoblast migration.

Migration and subsequent invasion of extravillous trophoblasts into the uterus is essential for proper formation of the placenta. Disruption of these processes may result in poor pregnancy outcomes including preeclampsia, placenta accreta, fetal growth restriction, or fetal death. Currently, there are several methods for quantifying cell migration and invasion in vitro, each with limitations.

Mechanism-driven modeling of chemical hepatotoxicity using structural alerts and an in vitro screening assay.

Traditional experimental approaches to evaluate hepatotoxicity are expensive and time-consuming. As an advanced framework of risk assessment, adverse outcome pathways (AOPs) describe the sequence of molecular and cellular events underlying chemical toxicities. We aimed to develop an AOP that can be used to predict hepatotoxicity by leveraging computational modeling and in vitro assays.

Transporters and Toxicity: Insights From the International Transporter Consortium Workshop 4.

Over the last decade, significant progress been made in elucidating the role of membrane transporters in altering drug disposition, with important toxicological consequences due to changes in localized concentrations of compounds. The topic of "Transporters and Toxicity" was recently highlighted as a scientific session at the International Transporter Consortium (ITC) Workshop 4 in 2021. The current white paper is not intended to be an extensive review on the topic of transporters and toxicity but an opportunity to highlight aspects of the role of transporters in various toxicities with clinically relevant implications as covered during the session.