Purpose: Several oral multikinase inhibitors are known to interact in vitro with the human ATP-binding cassette transporter ABCC4 (MRP4), but the in vivo relevance of this interaction remains poorly understood. We hypothesized that host ABCC4 activity may influence the pharmacokinetic profile of dasatinib and subsequently affect its antitumor properties.
Experimental Design: Transport of dasatinib was studied in cells transfected with human ABCC4 or the ortholog mouse transporter, Abcc4. Pharmacokinetic studies were done in wild-type and Abcc4-null mice. The influence of Abcc4 deficiency on dasatinib efficacy was evaluated in a model of Ph(+) acute lymphoblastic leukemia by injection of luciferase-positive, p185(BCR-ABL)-expressing Arf(-/-) pre-B cells.
Results: Dasatinib accumulation was significantly changed in cells overexpressing ABCC4 or Abcc4 compared with control cells (P < 0.001). Deficiency of Abcc4 in vivo was associated with a 1.75-fold decrease in systemic exposure to oral dasatinib, but had no influence on the pharmacokinetics of intravenous dasatinib. Abcc4 was found to be highly expressed in the stomach, and dasatinib efflux from isolated mouse stomachs ex vivo was impaired by Abcc4 deficiency (P < 0.01), without any detectable changes in gastric pH. Abcc4-null mice receiving dasatinib had an increase in leukemic burden, based on bioluminescence imaging, and decreased overall survival compared with wild-type mice (P = 0.048).
Conclusions: This study suggests that Abcc4 in the stomach facilitates the oral absorption of dasatinib, and it possibly plays a similar role for other orally administered substrates, such as acetylsalicylic acid. This phenomenon also provides a mechanistic explanation for the malabsorption of certain drugs following gastric resection.
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http://dx.doi.org/10.1158/1078-0432.CCR-13-0980 | DOI Listing |
Plant Physiol
January 2025
Assistant Features Editor, Plant Physiology, American Society of Plant Biologists, Rockville, USA.
Nat Genet
January 2025
Frontiers Science Center for Molecular Design Breeding (MOE); State Key Laboratory of Animal Biotech Breeding; College of Animal Science and Technology, China Agricultural University, Beijing, China.
Ongoing efforts to improve sheep reference genome assemblies still leave many gaps and incomplete regions, resulting in a few common failures and errors in genomic studies. Here, we report a 2.85-Gb gap-free telomere-to-telomere genome of a ram (T2T-sheep1.
View Article and Find Full Text PDFJ Hazard Mater
December 2024
Department of Occupational and Environmental Health, School of Public Health, Wuhan University, Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuhan 430071, China; Research Center of Public Health, Renmin Hospital of Wuhan University, Wuhan University, Wuhan 430060, China; Hubei Provincial Center for Disease Control and Prevention & NHC Specialty Laboratory of Food Safety Risk Assessment and Standard Development, Wuhan 430079, China; Hubei Key Laboratory of Biomass Resource Chemistry and Environmental Biotechnology, Wuhan University, Wuhan 430072, China. Electronic address:
Prenatal exposure to hazardous environmental pollutants is a critical global concern due to their confirmed presence in umbilical cord blood, indicating the ability of pollutants to cross the placental barrier and expose the fetus to harmful compounds. However, the transplacental transfer efficiencies (TTEs) of many pollutants remain underexplored. Herein, we developed a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method to quantitatively analyze 91 environmental pollutants, including 13 bisphenols (BPs), 18 organophosphorus flame retardants (OPFRs), 7 brominated and other flame retardants (BFRs), 34 phthalates (PAEs), and 19 per- and polyfluoroalkyl substances (PFASs), in paired maternal and cord serums.
View Article and Find Full Text PDFSci Rep
December 2024
Division of Plant Science and Technology, University of Missouri, Columbia, MO, 65211, USA.
The western corn rootworm (WCR), Diabrotica virgifera virgifera LeConte, has evolved resistance to nearly every management tactic utilized in the field. This study investigated the resistance mechanisms in a WCR strain resistant to the Bacillus thuringiensis (Bt) protein eCry3.1Ab using dsRNA to knockdown WCR midgut genes previously documented to be associated with the resistance.
View Article and Find Full Text PDFPlant Physiol
December 2024
Graduate School of Bioagricultural Sciences, Nagoya University, Chikusa, Nagoya 464-8601, Japan.
The directional and sequential flow of cytokinin in plants is organized by a complex network of transporters. Genes involved in several aspects of cytokinin transport have been characterized; however, much of the elaborate system remains elusive. In this study, we used a transient expression system in tobacco (Nicotiana benthamiana) leaves to screen Arabidopsis (Arabidopsis thaliana) transporter genes and isolated ATP-BINDING CASSETTE TRANSPORTER C4 (ABCC4).
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