Plasma elimination of cholyl‐lysyl‐fluorescein (CLF): a pilot study in patients with liver cirrhosis

Milkiewicz, Piotr; Saksena, Sushma; Cardenas, Teresa; Mills, Charles O.; Elias, Elwyn

doi:10.1034/j.1600-0676.2000.020004330.x

Cited by 14 publications

(16 citation statements)

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“…For example, although ABCB11 and ABCC2 protein levels and localization were found to be maintained in primary biliary cirrhosis stages I and II (Zollner et al, 2003(Zollner et al, , 2007, reduced protein levels and a disruption of canalicular localization have been reported for ABCC2 in advanced primary biliary cirrhosis (stages III and IV) (Kullak-Ublick et al, 2002;Kojima et al, 2003). In a pilot study CLF elimination was analyzed in liver cirrhosis patients and seemed to be impaired in comparison with healthy volunteers (Milkiewicz et al, 2000). Those cirrhotic patients suffered from high serum bilirubin and bile salt level, indicative of a cholestatic situation.…”

Section: Discussionmentioning

confidence: 99%

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Hepatic Transport Mechanisms of Cholyl-l-Lysyl-Fluorescein

Waart

Häusler²,

Vlaming³

et al. 2010

J Pharmacol Exp Ther

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Cholyl-L-lysyl-fluorescein (CLF) is a fluorescent bile salt derivative that is being developed as an agent for determining in vivo liver function. However, the mechanisms of uptake and excretion by hepatocytes have not been rigorously studied. We have directly assessed the transport capacity of various hepatobiliary transporters for CLF. Uptake experiments were performed in Chinese hamster ovary cells transfected with human NTCP, OATP1B1, OATP1B3, and OATP2B1. Conversely, excretory systems were tested with plasma membrane vesicles from Sf21 insect cells expressing human ABCB11, ABCC2, ABCC3, and ABCG2. In addition, plasma clearance and biliary excretion of CLF were examined in wild-type, Abcc2(Ϫ/Ϫ), and Abcc3(Ϫ/Ϫ) mice. Human Na ϩ -dependent taurocholic-cotransporting polypeptide (NTCP) and ATP-binding cassette B11 (ABCB11) were incapable of transporting CLF. In contrast, high-affinity transport of CLF was observed for organic anion-transporting polypeptide 1B3 (OATP1B3), ABCC2, and ABCC3 with K m values of 4.6 Ϯ 2.7, 3.3 Ϯ 2.0, and 3.7 Ϯ 1.0 M, respectively. In Abcc2(Ϫ/Ϫ) mice biliary excretion of CLF was strongly reduced compared with wild-type mice. This resulted in a much higher hepatic retention of CLF in Abcc2(Ϫ/Ϫ) versus wild-type mice: 64 versus 1% of the administered dose (2 h after administration). In mice intestinal uptake of CLF was negligible compared with that of taurocholate. Our conclusion is that human NTCP and ABCB11 are incapable of transporting CLF, whereas OATP1B3 and ABCC2/Abcc2 most likely mediate hepatic uptake and biliary excretion of CLF, respectively. CLF can be transported back into the blood by ABCC3. Enterohepatic circulation of CLF is minimal. This renders CLF suitable as an agent for assessing in vivo liver function.

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Section: Discussionmentioning

confidence: 99%

“…Cholyl-L-lysyl-fluorescein (CLF) is a fluorescent bile salt and has been introduced as a potential agent for assessing in vivo liver function (Milkiewicz et al, 2000). However, the transport systems involved in hepatic handling of CLF have not been investigated in molecular detail so far.…”

mentioning

confidence: 99%

Hepatic Transport Mechanisms of Cholyl-l-Lysyl-Fluorescein

Waart

Häusler²,

Vlaming³

et al. 2010

J Pharmacol Exp Ther

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“…Fluorescently labeled bile salts have been suggested as liver function indicators on the basis of a pilot study that demonstrated reduced clearance of cholyllysyl-fluorescein (CLF) in patients with liver cirrhosis (Milkiewicz et al, 2000). CLF is not a substrate of the major bile salt transporters NTCP and bile salt export pump (BSEP), but of OATP1B3, weakly of OATP1B1, and of the efflux transporters MRP2 and MRP3 (table 1).…”

Section: Fluorescently Labeled Bile Saltsmentioning

confidence: 99%

“…Hence, transport proteins are key molecular components of the hepatocellular detoxification system (phase 0 and phase III) and consequently of liver function tests. Liver function tests utilizing exogenous indicators such as indocyanine green (ICG), bromosulphophthalein (BSP), fluorescent bile salt derivatives, agents for magnetic resonance imaging (MRI), single photon emission computed tomography (SPECT), or breath tests have been developed to complement the use of endogenous indicators (de Graaf et al, 2010a;Milkiewicz et al, 2000;Millet et al, 2011;Sakka, 2007). Preoperative dynamic liver function tests are part of the routine assessment of patients scheduled for liver resection in many centers (Breitenstein et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

The emerging role of transport systems in liver function tests

Stieger

Heger

Graaf

et al. 2012

European Journal of Pharmacology

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Liver function tests are of critical importance for the management of patients with severe or terminal liver disease. They are also used as prognostic tools for planning liver resections. In recent years many transport systems have been identified that also transport substances employed in liver function tests. Such substances include endogenous bilirubin or exogenously administered indocyanine green, agents for magnetic resonance imaging, agents for single photon emission computed tomography or agents for breath tests. The increasing functional and molecular information on the respective transport systems should improve the management and as a result the outcome of patients scheduled for liver surgery or transplantation. To achieve the latter goal, clinical studies that assess individual patients' liver function over the course of their disease with liver function tests are needed to firmly establish and validate recently introduced and novel liver function markers. The emerging role of transport systems in liver function tests Bruno Stieger is supported by grant # 31003A_124652 from the Swiss National Science foundation. AbstractLiver function tests are of critical importance for the management of patients with severe or terminal liver disease. They are also used as prognostic tools for planning liver resections. In recent years many transport systems have been identified, that also transport substances employed in liver function tests. Such substances include endogenous bilirubin or exogenously administered indocyanine green, agents for magnetic resonance imaging, agents for single photon emission computed tomography or agents for breath tests. The increasing functional and molecular information on the respective transport systems should improve the management and as a result the outcome of patients scheduled for liver surgery or transplantation. To achieve the latter goal, clinical studies that assess individual patients liver function over the course of their disease with liver function testes are needed to firmly establish and validate recently introduced and novel liver function markers.

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“…Measurement of drug inhibition of CLF transport has been used to discern cholestatic mechanisms [61,62], and a positive association has been demonstrated between cholestatic DILI in humans and inhibition of apical CLF efflux from rat hepatocytes in sandwich culture [63]. Moreover, CLF has been shown to have 100% sensitivity when used to detect liver cirrhosis in patient cohorts [64,65].…”

Section: Petmentioning

confidence: 99%

Noninvasive Preclinical and Clinical Imaging of Liver Transporter Function Relevant to Drug-Induced Liver Injury

Kenna

Waterton

Baudy

et al. 2018

Methods in Pharmacology and Toxicology

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Imaging technologies can evaluate many different biological processes in vitro (in cell culture models) and in vivo (in animals and humans), and many are used routinely in investigation of human liver diseases. Some of these methods can help understand liver toxicity caused by drugs in vivo in animals, and druginduced liver injury (DILI) which arises in susceptible humans. Imaging could aid assessment of the relevance to humans in vivo of toxicity caused by drugs in animals (animal/human translation), plus toxicities observed using in vitro model systems (in vitro/in vivo translation). Technologies and probe substrates for quantitative evaluation of hepatobiliary transporter activities are of particular importance. This is due to the key role played by sinusoidal transporter mediated hepatic uptake in DILI caused by many drugs, plus the strong evidence that inhibition of the hepatic bile salt export pump (BSEP) can initiate DILI. Imaging methods for investigation of these processes are reviewed in this chapter, together with their scientific rationale, and methods of quantitative data analysis. In addition to providing biomarkers for investigation of DILI, such approaches could aid the evaluation of clinically relevant drug-drug interactions mediated via hepatobiliary transporter perturbation.

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Plasma elimination of cholyl‐lysyl‐fluorescein (CLF): a pilot study in patients with liver cirrhosis

Cited by 14 publications

References 0 publications

Hepatic Transport Mechanisms of Cholyl-l-Lysyl-Fluorescein

Hepatic Transport Mechanisms of Cholyl-l-Lysyl-Fluorescein

The emerging role of transport systems in liver function tests

Noninvasive Preclinical and Clinical Imaging of Liver Transporter Function Relevant to Drug-Induced Liver Injury

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