Characterization of the Intestinal and Hepatic Uptake/Efflux Transport of the Magnetic Resonance Imaging Contrast Agent Gadolinium-Ethoxylbenzyl-Diethylenetriamine-Pentaacetic Acid

Jia, Jia; Puls, Dorothee; Oswald, Stefan; Jedlitschky, Gabriele; Kühn, Jens Peter; Weitschies, Werner; Hosten, Norbert; Siegmund, Werner; Keiser, Markus

doi:10.1097/rli.0b013e3182a70043

Cited by 44 publications

(43 citation statements)

References 54 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The functionality of the ABCB1-transfected cells was verified by an in vitro accumulation assay using calcein-AM [41]. Stable transfected MDCK2-ABCC2 cells were generated and characterized as described previously [42].…”

Section: Permeability Of Flupirtine and D13223 In Mdck2 Cells Transfementioning

confidence: 99%

Metabolic activation and analgesic effect of flupirtine in healthy subjects, influence of the polymorphic NAT2, UGT1A1 and GSTP1

Siegmund

Modeß

Scheuch

et al. 2015

Brit J Clinical Pharma

Self Cite

View full text Add to dashboard Cite

AIMSThe rare association of flupirtine with liver injury is most likely caused by reactive quinone diimines and their oxidative formation may be influenced by the activities of N-acetyltransferases (NAT) that conjugate the less toxic metabolite D13223, and by glucuronosyltransferases (UGT) and glutathione S-transferases (GST) that generate stable terminal glucuronides and mercapturic acid derivatives, respectively. The influence of genetic polymorphisms of NAT2, UGT1A1 and GSTP1 on generation of the terminal mercapturic acid derivatives and analgesic effects was evaluated to identify potential genetic risk factors for hepatotoxicity of flupirtine. METHODSMetabolic disposition of flupirtine was measured after intravenous administration (100 mg), after swallowing an immediate-release (IR) tablet (100 mg) and after repeated administration of modified release (MR) tablets (400 mg once daily 8 days) in 36 selected healthy subjects. Analgesic effects were measured using pain models (delayed onset of muscle soreness, electric pain). RESULTSFlupirtine IR was rapidly but incompletely absorbed (∼72%). Repeated administration of flupirtine MR showed lower bioavailability (∼60%). Approximately 12% of bioavailable flupirtine IR and 8% of bioavailable flupiritine MR was eliminated as mercapturic acid derivatives into the urine independent of the UGT1A1, NAT2 and GSTP1 genotype. Carriers of variant GSTP1 alleles showed lower bioavailability but increased intestinal secretion of flupirtine and increased efficiency in experimental pain. Flupirtine was not a substrate for ABCB1 and ABCC2.

show abstract

Section: Permeability Of Flupirtine and D13223 In Mdck2 Cells Transfementioning

confidence: 99%

Metabolic activation and analgesic effect of flupirtine in healthy subjects, influence of the polymorphic NAT2, UGT1A1 and GSTP1

Siegmund

Modeß

Scheuch

et al. 2015

Brit J Clinical Pharma

Self Cite

View full text Add to dashboard Cite

show abstract

“…The biliary excretion of gadoxetate occurs primarily via the multidrug resistance-associated protein (mrp2) in the canalicular membrane of the hepatocyte. Gadoxetate transport and efflux in rat liver have been previously characterized to confirm hepatic uptake, and efflux occurs in rat hepatocytes (Jia et al 2014;Ogawa et al 2014). Drugs that are known inhibitors of the uptake transporters for gadoxetate will inhibit the increase in liver signal intensity (SI, uptake) after gadoxetate injection.…”

Section: Introductionmentioning

confidence: 99%

Hepatic Phospholipidosis Is Associated with Altered Hepatobiliary Function as Assessed by Gadoxetate Dynamic Contrast–enhanced Magnetic Resonance Imaging

et al. 2015

View full text Add to dashboard Cite

To determine if amiodarone induces hepatic phospholipidosis (PLD) sufficient to detect changes in hepatobiliary transporter function as assessed by gadoxetate dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), rats were orally dosed with vehicle (1% methyl cellulose) or amiodarone (300 mg/kg/day) for 7 consecutive days. Gadoxetate DCE-MRI occurred at baseline, day 7, and following a 2-week washout of amiodarone. At day 7, the gadoxetate washout rate was significantly decreased compared to the vehicle group. Blood chemistry analysis revealed no significant changes in liver enzymes (alanine aminotransferase [ALT]/aspartate aminotransferase [AST]/alkaline phosphatase [ALP]), bilirubin, or bile acids between vehicle or amiodarone groups. Hepatic PLD was confirmed in all rats treated with amiodarone at day 7 by transmission electron microscopy. Following the 2-week washout, there was no ultrastructural evidence of hepatic PLD in rats and the gadoxetate washout rate returned to baseline levels. This is the first study to show the application of gadoxetate DCE-MRI to detect hepatobiliary functional changes associated with PLD and offer a potential new technique with clinical utility in patients suspected of having PLD. These results also suggest PLD itself has functional consequences on hepatobiliary function in the absence of biomarkers of toxicity, given the cause/effect relationship between PLD and function has not been fully established.

show abstract

“…BOPTA is a substrate of rOATP1A1, rOATP1A4, rOATP1B1, and rMRP2 (57), and its hepatic accumulation is inhibited in a dose-dependent manner by the OATP inhibitor rifampin (91) (Table III). EOB-DTPA is a substrate of OATP1B1, OATP1B3, the human sodiumtaurocholate-co-transporting polypeptide (hNTCP) (64), and the ABC transporters MRP2 and MRP3 (59) (Table III). These compounds enter the hepatocytes through sinusoidal OATPs and are removed through biliary excretion or efflux back into sinusoids by MRP2 and MRP3, respectively (87).…”

Section: Mrimentioning

confidence: 99%

Molecular Imaging of Membrane Transporters’ Activity in Cancer: a Picture is Worth a Thousand Tubes

Mann

Semenenko

Meir

et al. 2015

AAPS J

View full text Add to dashboard Cite

Abstract. Molecular imaging allows the non-invasive assessment of membrane transporter expression and function in living subjects. Such technologies have the potential to become diagnostic and prognostic tools, allowing detection, localization, and prediction of response of tumors and their metastases to therapy. Beyond tumors, imaging can also help understand the role of transporters in adverse drug effects and drug clearance. Here, we review molecular imaging technologies that monitor transporter-mediated processes. We emphasize emerging probe substrates and potential clinical applications of imaging the function of membrane transporters in cancer.

show abstract

Characterization of the Intestinal and Hepatic Uptake/Efflux Transport of the Magnetic Resonance Imaging Contrast Agent Gadolinium-Ethoxylbenzyl-Diethylenetriamine-Pentaacetic Acid

Abstract: The nonmetabolized Gd-EOB-DTPA may have some potentials to be used as a probe-contrast agent to evaluate transporter-mediated mechanisms along the enterohepatic absorption route for drugs by functional visualization in vivo.

Cited by 44 publications

References 54 publications

Metabolic activation and analgesic effect of flupirtine in healthy subjects, influence of the polymorphic NAT2, UGT1A1 and GSTP1

Metabolic activation and analgesic effect of flupirtine in healthy subjects, influence of the polymorphic NAT2, UGT1A1 and GSTP1

Hepatic Phospholipidosis Is Associated with Altered Hepatobiliary Function as Assessed by Gadoxetate Dynamic Contrast–enhanced Magnetic Resonance Imaging

Molecular Imaging of Membrane Transporters’ Activity in Cancer: a Picture is Worth a Thousand Tubes

Contact Info

Product

Resources

About