Sodium fluorescein is a probe substrate for hepatic drug transport mediated by OATP1B1 and OATP1B3

Bruyn, Tom De; Fattah, Sarinj; Stieger, Bruno; Augustijns, Patrick; Annaert, Pieter

doi:10.1002/jps.22694

Cited by 78 publications

(71 citation statements)

References 41 publications

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“…The organic anion fluorescein has been widely used as a fluorescent probe in studies of hepatic transport (2, 24) and has recently been identified as a specific substrate of human and rat organic anion (OATP/Oatp) transporters (2). In previous studies (1), we demonstrated that quantitative intravital microscopy of the livers of rats injected with fluorescein can be used to sensi- Renal function in 5/6th nephrectomy (5/6N) and control rats.…”

Section: Resultsmentioning

confidence: 97%

“…The ability to dissect the individual steps of transport makes this method capable of resolving the effects of CKD on hepatocyte uptake, as well as on overall rates of transport to bile canaliculi. Here, we apply this approach to evaluate the effects of CKD on the hepatic transport of fluorescein, a fluorescent substrate specific for Oatp and Mrp2 transporters (2,29) and to test the hypothesis that Oatp-mediated transport is reduced in the 5/6N rat, resulting in reduced hepatic transport of organic anions.…”

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confidence: 99%

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Effects of chronic kidney disease on liver transport: quantitative intravital microscopy of fluorescein transport in the rat liver

Ryan

Dunn

Decker

2014

American Journal of Physiology-Regulatory, Integrative and Comp

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Ryan JC, Dunn KW, Decker BS. Effects of chronic kidney disease on liver transport: quantitative intravital microscopy of fluorescein transport in the rat liver. Am J Physiol Regul Integr Comp Physiol 307: R1488 -R1492, 2014. First published October 22, 2014 doi:10.1152/ajpregu.00371.2014.-Clinical studies indicate that hepatic drug transport may be altered in chronic kidney disease (CKD). Uremic solutes associated with CKD have been found to alter the expression and/or activity of hepatocyte transporters in experimental animals and in cultured cells. However, given the complexity and adaptability of hepatic transport, it is not clear whether these changes translate into significant alterations in hepatic transport in vivo. To directly measure the effect of CKD on hepatocyte transport in vivo, we conducted quantitative intravital microscopy of transport of the fluorescent organic anion fluorescein in the livers of rats following 5/6th nephrectomy, an established model of CKD. Our quantitative analysis of fluorescein transport showed that the rate of hepatocyte uptake was reduced by ϳ20% in 5/6th nephrectomized rats, consistent with previous observations of Oatp downregulation. However, the overall rate of transport into bile canaliculi was unaffected, suggesting compensatory changes in Mrp2-mediated secretion. Our study suggests that uremia resulting from 5/6th nephrectomy does not significantly impact the overall hepatic clearance of an Oatp substrate. chronic kidney disease; uremia; cytochrome P-450; hepatic transport; Mrp2; Oatp; sodium fluorescein PATIENTS WITH END-STAGE RENAL disease (ESRD) receiving dialysis take on average 12 medications to manage the complications of their renal failure and their comorbid disease, which places them at a substantial risk for adverse drug events (8,12,13). Currently, modifications in drug dosing to improve safety for ESRD patients have largely been confined to those medications excreted renally. This has likely improved the safety of these medications for the ESRD population, yet it remains an incomplete approach, since it does not include the hepatically metabolized medications. This oversight is significant because evidence increasingly indicates that hepatic drug metabolism and transport are reduced in patients with [14][15][16][17][18][19][20][21][22][25][26][27][28]30). Consequently, administering the full dose of a hepatically metabolized medication may place an ESRD patient at similar risk for an adverse drug event as administering the full dose of a renally eliminated medication.Experimental evidence suggests multiple mechanisms by which uremic solutes might influence hepatic drug disposition (20,25). Studies from the Pichette laboratory demonstrated that the activity and expression of cytochrome P-450 (CYP450) was reduced in the 5/6th nephrectomy (5/6N) rat model of chronic renal failure (6, 10, 11). Their work elucidated a direct role for uremic solutes with the observation that CYP450 activity and expression were reduced in primary rat hepatocytes incubated wit...

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Section: Resultsmentioning

confidence: 97%

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confidence: 99%

Effects of chronic kidney disease on liver transport: quantitative intravital microscopy of fluorescein transport in the rat liver

Ryan

Dunn

Decker

2014

American Journal of Physiology-Regulatory, Integrative and Comp

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“…With minimal toxicity (LD 50 of 1 g/kg in rats), sodium fluorescein has been frequently used as a fluorescent probe in intravital microscopy studies of hepatic transport, 34,35,39,40,44,45 although it has only recently been demonstrated to be a specific substrate of the human and rat organic anion (OAT/Oat) transporters. 46 Like many other substrates transported by hepatocytes, fluorescein is rapidly glucuronidated in the cytosol following hepatocyte uptake, [47][48][49] making it an appropriate model probe for the anion glucuronate transporters Mrp2 and Mrp3.…”

Section: Resultsmentioning

confidence: 99%

Quantitative intravital microscopy of hepatic transport

et al. 2012

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“…12,13 Several studies have illustrated that HIV PI inhibit the in vitro cellular uptake of OATP1B probe substrates like estradiol-17β-D-glucuronide, CGamF and sodium fluorescein. [14][15][16][17] Moreover, it has been suggested that inhibition of these membrane transporters contributes to clinically important antiretroviral drug-drug interactions, for example with cerivastatin and atorvastatin. 18 While these examples certainly illustrate the clinical relevance of OATP modulation by HIV PI, the concept of meaningful OATPmediated transport of HIV PI remains controversial.…”

Section: Introductionmentioning

confidence: 99%

Clearance Prediction of HIV Protease Inhibitors in Man: Role of Hepatic Uptake

Bruyn

Stieger

Augustijns

et al. 2016

Journal of Pharmaceutical Sciences

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The aim of this work was to explore the contribution of the organic anion transporting polypeptide-1B (OATP1B) drug transporters in the hepatic clearance (Cl) of all marketed HIV protease inhibitors (PI) in humans. HIV PI uptake rates in OATP1B1/1B3-transfected Chinese hamster ovary cells were converted to uptake Cl values in human hepatocytes via a relative activity factor, which was determined by comparing uptake of known substrates between OATP1B1/3-transfected cells and human hepatocytes. Metabolic Cl values were determined in human liver microsomes. In vivo hepatic Cl values were calculated either by combining drug uptake and metabolism or based on one of these individual Cl processes and compared with published in vivo hepatic Cl values. Excellent in vitro-in vivo correlation (R(2) = 0.85) was observed when only uptake Cl values were used, but not when only metabolic Cl was used (R(2) = 0.40). The correlation did not improve when both processes were taken into account (R(2) = 0.85). PBPK models confirmed the remarkable sensitivity of predicted exposure to hepatic drug uptake, indicating a key role for OATP1B1/3 in hepatic disposition of several HIV PI in man. This may contribute to the interindividual variability in systemic and hepatic exposure to these drugs in the clinic.

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Sodium fluorescein is a probe substrate for hepatic drug transport mediated by OATP1B1 and OATP1B3

Cited by 78 publications

References 41 publications

Effects of chronic kidney disease on liver transport: quantitative intravital microscopy of fluorescein transport in the rat liver

Effects of chronic kidney disease on liver transport: quantitative intravital microscopy of fluorescein transport in the rat liver

Quantitative intravital microscopy of hepatic transport

Clearance Prediction of HIV Protease Inhibitors in Man: Role of Hepatic Uptake

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