Troglitazone sulfate (TGZS) is the major metabolite of troglitazone (TGZ), an antidiabetic agent, and thought to be a cause of the cholestasis induced by TGZ. The aim of the present study is to elucidate the involvement of breast cancer resistance protein (BCRP/ABCG2) in the hepatic disposition of TGZS. The basal-to-apical transport of TGZS was enhanced in organic anion transporting polypeptide 1B1-expressing Madin-Darby canine kidney II cells by infection of recombinant adenovirus harboring human BCRP and mouse Bcrp cDNA. TGZS was given to wild-type and Bcrp (-/-) mice by constant infusion. Biliary excretion is the predominant elimination pathway of TGZS in wild-type mice, and the biliary excretion clearance of TGZS with regard to the hepatic concentration was reduced to 30% of the control in Bcrp (-/-) mice. However, plasma and hepatic concentrations were unchanged, suggesting induction of compensatory mechanisms in Bcrp (-/-) mice for the elimination of TGZS. Involvement of BCRP in the intestinal efflux transport of TGZS was examined using everted sacs. The mucosal efflux clearance of TGZS showed only a slight reduction (15% reduction) in Bcrp (-/-) mice. Our results suggest that BCRP plays a major role in the biliary excretion but a minor role in the intestinal transport of TGZS.
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http://dx.doi.org/10.1124/dmd.106.012567 | DOI Listing |
Expert Opin Drug Metab Toxicol
January 2025
Institut de R&D Servier, Paris-Saclay, F-91190 Gif-sur-Yvette, France.
Introduction: Drug-mediated inhibition of bile salt efflux transporters may cause liver injury. In vitro prediction of drug effects toward canalicular and/or sinusoidal efflux of bile salts from human hepatocytes is therefore a major issue, which can be addressed using liver cell-based assays.
Area Covered: This review, based on a thorough literature search in the scientific databases PubMed and Web of Science, provides key information about hepatic transporters implicated in bile salt efflux, the human liver cell models available for investigating functional inhibition of bile salt efflux, the different methodologies used for this purpose, and the modes of expression of the results.
Food Chem Toxicol
January 2025
INSERM, Univ Rennes, INRAE, Institut NUMECAN (Nutrition, Métabolismes et Cancer) UMR_A 1341, UMR_S 1317, F-35000, Rennes, France; Laboratoire de toxicologie biologique et Médico-légale, CHU Rennes, Rennes, France.
Objective: Recently, the pig liver model perfused ex vivo using a normothermic machine perfusion (NMP) has been proposed as a suitable model to study xenobiotic metabolism and biliary excretion. The aim of our study is to describe the metabolism of NPS such as cathinones (with a focus on 4-Cl-PVP and eutylone) in blood and bile, using a normothermic perfused pig liver model.
Methods: Livers (n = 4) from male large white pigs, 3-4 months of age and weighing approximately 75-80 kg, were harvested and reperfused onto an NMP (LiverAssist®, XVIVO) using autologous whole blood at 38 °C.
J Viral Hepat
February 2025
Liver Unit, Birmingham Children's Hospital, Birmingham Women's and Children's NHS Foundation Trust, Birmingham, UK.
Hepatitis B elimination objectives can only be realised if new patient linkage to care is matched by long-term patient retention in care. We previously showed in adult chronic hepatitis B (CHB) patients that retention in care was inferior in younger patients and in patients from non-Asian ethnicities. The present study explores further the rates and determinants of loss to follow-up in a cohort of 271 young patients (aged 16-21 years at baseline).
View Article and Find Full Text PDFCPT Pharmacometrics Syst Pharmacol
January 2025
Department of Pharmacy, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
Rheumatoid arthritis (RA) is a major public health concern, which can cause serious outcomes. Low-dose methotrexate (MTX) is a cornerstone in RA treatment, but there is significant heterogeneity in clinical response. To evaluate underlying sources of pharmacokinetic variability and clinical response of MTX, a physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) model was developed using PK-sim and Mobi (version 11.
View Article and Find Full Text PDFJ Gastrointestin Liver Dis
December 2024
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
Background And Aims: Wilson disease (WD) results in the defective incorporation of copper into ceruloplasmin as well as decreased biliary copper excretion. Secondary iron overload has also been associated with WD; however, the prevalence is currently unknown. This study aims to determine the prevalence of potential secondary iron overload in patients suspected to have WD.
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