Targeting a xenobiotic transporter to ameliorate vincristine-induced sensory neuropathy.

Vincristine is a widely used chemotherapeutic drug for the treatment of multiple malignant diseases that causes a dose-limiting peripheral neurotoxicity. There is no clinically effective preventative treatment for vincristine-induced sensory peripheral neurotoxicity (VIPN), and mechanistic details of this side effect remain poorly understood. We hypothesized that VIPN is dependent on transporter-mediated vincristine accumulation in dorsal root ganglion neurons.

MATE1 Deficiency Exacerbates Dofetilide-Induced Proarrhythmia.

Dofetilide is a rapid delayed rectifier potassium current inhibitor widely used to prevent the recurrence of atrial fibrillation and flutter. The clinical use of this drug is associated with increases in QTc interval, which predispose patients to ventricular cardiac arrhythmias. The mechanisms involved in the disposition of dofetilide, including its movement in and out of cardiomyocytes, remain unknown.

and Inhibition of MATE1 by Tyrosine Kinase Inhibitors.

The membrane transport of many cationic prescription drugs depends on facilitated transport by organic cation transporters of which several members, including OCT2 (), are sensitive to inhibition by select tyrosine kinase inhibitors (TKIs). We hypothesized that TKIs may differentially interact with the renal transporter MATE1 () and influence the elimination and toxicity of the MATE1 substrate oxaliplatin. Interactions with FDA-approved TKIs were evaluated in transfected HEK293 cells, and pharmacokinetic studies were performed in wild-type, MATE1-deficient, and OCT2/MATE1-deficient mice.

Intentional Modulation of Ibrutinib Pharmacokinetics through CYP3A Inhibition.

Ibrutinib (Imbruvica; PCI-32765) is an orally administered inhibitor of Bruton's tyrosine kinase that has transformed the treatment of B-cell malignancies. However, ibrutinib has very low oral bioavailability that contributes to significant variability in systemic exposure between patients, and this has the potential to affect both efficacy and toxicity. We hypothesized that the oral bioavailability of ibrutinib is limited by CYP3A isoform-mediated metabolism, and that this pathway can be inhibited to improve the pharmacokinetic properties of ibrutinib.

Gilteritinib Inhibits Glutamine Uptake and Utilization in -ITD-Positive AML.

Acute myeloid leukemia (AML) with an internal tandem duplication (-ITD) mutation is an aggressive hematologic malignancy associated with frequent relapse and poor overall survival. The tyrosine kinase inhibitor gilteritinib is approved for the treatment of relapse/refractory AML with mutations, yet its mechanism of action is not completely understood. Here, we sought to identify additional therapeutic targets that can be exploited to enhance gilteritinib's antileukemic effect.

Development, validation, and application of an LC-MS/MS method for the determination of the AXL/FLT3 inhibitor gilteritinib in mouse plasma.

A simple, fast and precise LC-MS/MS method for the quantitation of the tyrosine kinase inhibitor gilteritinib was developed and validated for micro-volumes of mouse plasma. The assay procedure involved a one-step extraction of gilteritinib and the internal standard [H]-gilteritinib with acetonitrile. An Accucore aQ column was used to separate analytes using a gradient elution delivered at a flow rate of 0.

Contribution of membrane transporters to chemotherapy-induced cardiotoxicity.

Membrane transporters play a key role in determining the pharmacokinetic profile, therapeutic safety, and efficacy of many chemotherapeutic drugs by regulating cellular influx and efflux. Rapidly emerging evidence has shown that tissue-specific expression of transporters contributes to local drug accumulation and drug-drug interactions and that functional alterations in these transporters can directly influence an individual's susceptibility to drug-induced toxicity. Comprehending the complex mechanism of transporter function in regulating drug distribution in tissues, such as the heart, is necessary in order to acquire novel therapeutic strategies aimed at evading unwanted drug accumulation and toxicities and to ameliorate the safety of current therapeutic regimens.

Influence of YES1 Kinase and Tyrosine Phosphorylation on the Activity of OCT1.

Organic cation transporter 1 (OCT1) is a transporter that regulates the hepatic uptake and subsequent elimination of diverse cationic compounds. Although OCT1 has been involved in drug-drug interactions and causes pharmacokinetic variability of many prescription drugs, details of the molecular mechanisms that regulate the activity of OCT1 remain incompletely understood. Based on an unbiased phospho-proteomics screen, we identified OCT1 as a tyrosine-phosphorylated transporter, and functional validation studies using genetic and pharmacological approaches revealed that OCT1 is highly sensitive to small molecules that target the protein kinase YES1, such as dasatinib.

Rapid quantification of vincristine in mouse plasma using ESI-LC-MS/MS: Application to pharmacokinetic studies.

A simple, rapid, and sensitive LC-MS/MS method for determining concentrations of the anticancer alkaloid vincristine in micro volumes of mouse plasma was developed and validated in positive ion mode. Separation of vincristine and the internal standard [H]-vincristine was achieved on an Accucore aQ column with a gradient mobile phase delivered at a flow rate of 0.4 mL/min and a run time of 2.

Regulation of OATP1B1 Function by Tyrosine Kinase-mediated Phosphorylation.

Purpose: OATP1B1 (SLCO1B1) is the most abundant and pharmacologically relevant uptake transporter in the liver and a key mediator of xenobiotic clearance. However, the regulatory mechanisms that determine OATP1B1 activity remain uncertain, and as a result, unexpected drug-drug interactions involving OATP1B1 substrates continue to be reported, including several involving tyrosine kinase inhibitors (TKI).

Experimental Design: OATP1B1-mediated activity in overexpressing HEK293 cells and hepatocytes was assessed in the presence of FDA-approved TKIs, while rosuvastatin pharmacokinetics in the presence of an OATP1B1 inhibiting TKI were measured .

Targeting OCT3 attenuates doxorubicin-induced cardiac injury.

Doxorubicin is a commonly used anticancer agent that can cause debilitating and irreversible cardiac injury. The initiating mechanisms contributing to this side effect remain unknown, and current preventative strategies offer only modest protection. Using stem-cell-derived cardiomyocytes from patients receiving doxorubicin, we probed the transcriptomic landscape of solute carriers and identified organic cation transporter 3 (OCT3) (SLC22A3) as a critical transporter regulating the cardiac accumulation of doxorubicin.

Neuronal uptake transporters contribute to oxaliplatin neurotoxicity in mice.

Peripheral neurotoxicity is a debilitating condition that afflicts up to 90% of patients with colorectal cancer receiving oxaliplatin-containing therapy. Although emerging evidence has highlighted the importance of various solute carriers to the toxicity of anticancer drugs, the contribution of these proteins to oxaliplatin-induced peripheral neurotoxicity remains controversial. Among candidate transporters investigated in genetically engineered mouse models, we provide evidence for a critical role of the organic cation transporter 2 (OCT2) in satellite glial cells in oxaliplatin-induced neurotoxicity, and demonstrate that targeting OCT2 using genetic and pharmacological approaches ameliorates acute and chronic forms of neurotoxicity.

Role of transporters in toxicity induced by anticancer drugs.

Introduction: . Membrane transporters are integral to the maintenance of cellular integrity of all tissue and cell types. While transporters play an established role in the systemic pharmacokinetics of therapeutic drugs, tissue specific expression of uptake transporters can serve as an initiating mechanism that governs the accumulation and impact of cytotoxic drugs.

Murine Pharmacokinetic Studies.

Murine pharmacokinetics (PK) represents the absorption, distribution, metabolism, and elimination of drugs from the body, which helps to guide clinical studies, ultimately resulting in more effective drug treatment. The purpose of this protocol is to describe a serial bleeding protocol, obtaining blood samples at six time points from single mouse to yield a complete PK profile. This protocol has proved to be rapid, highly repeatable, and relatively easy to acquire.

Development and validation of a UPLC-MS/MS analytical method for dofetilide in mouse plasma and urine, and its application to pharmacokinetic study.

A novel method using UPLC with tandem mass-spectrometric detection (UPLC-MS/MS) with positive electrospray ionization was developed for the detection of the antiarrhythmic drug, dofetilide, in mouse plasma and urine. Protein precipitation was performed on 10 μL of plasma and 2 μL of urine samples using dofetilide-D4 as an internal standard, and separation of the analyte was accomplished on a C18 analytical column with the flow of 0.40 mL/min.

CNS Depressant and Antinociceptive Effects of Different Fractions of Pandanus Foetidus Roxb. Leaf Extract in Mice.

Background: Various parts of Pandanus foetidus Roxb. are used as traditional medicines. However, scientific reports concerning the effect of this plant on central nervous system (CNS) depression and analgesia are unavailable.

Evaluation of Antidiarrheal Activity of Methanolic Extract of Maranta arundinacea Linn. Leaves.

Diarrhea is one of the most common causes for thousands of deaths every year. Therefore, identification of new source of antidiarrheal drugs becomes one of the most prominent focuses in modern research. Our aim was to investigate the antidiarrheal and cytotoxic activities of methanolic extract of Maranta arundinacea linn.

Investigation of in vivo neuropharmacological effect of Alpinia nigra leaf extract.

Objective: To analyze in vivo neuro-pharmacological effects of Alpinia nigra as anxiety is a particular form of behavioral inhibition that occurs in response to novel environmental events.

Methods: In present study, the extract of Alpinia nigra was evaluated for its central nervous system depressant effect using mice behavioral models, such as hole cross, open field and thiopental sodium induced sleeping time tests for its sedative properties and an elevated plus-maze test for its anxiolytic potential, respectively.

Results: In anxiolytic study, the extract displayed increased percentage of entry into open arm at the dose of 400 and 200 mg/kg.