ALTERED HEPATOBILIARY DISPOSITION OF 5 (AND 6)-CARBOXY-2′,7′-DICHLOROFLUORESCEIN IN<i>Abcg2</i>(Bcrp1) AND<i>Abcc2</i>(Mrp2) KNOCKOUT MICE

Nezasa, Ken Ichi; Tian, Xianbin; Zamek‐Gliszczynski, Maciej J.; Patel, Nita; Raub, Thomas J.; Brouwer, Kim L. R.

doi:10.1124/dmd.105.007922

Cited by 49 publications

(55 citation statements)

References 31 publications

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“…3 in predicting the fold change in biliary, systemic, or hepatic exposure to polar metabolites formed in the liver. These data were generated in single-pass liver perfusion experiments in which the biliary and perfusate (systemic) recovery of substrates could be quantified directly (Takenaka et al, 1995;Xiong et al, 2002;Nezasa et al, 2006;Zamek-Gliszczynski et al, 2006b,c). Rodents genetically deficient in a specific transport protein were used to examine the impact of complete abro- Altered exposure/recovery of 4-methylumbelliferyl glucuronide (4MUG) in Mrp3 and Bcrp knockout mice (Tables 1-3) will be used to illustrate the application of the theoretical relationships.…”

Section: Resultsmentioning

confidence: 99%

“…Positive fold ⌬ values indicate an increase in exposure, whereas decreased exposure is denoted by a negative fold ⌬ value. All data points were calculated using mean values reported in the literature (Takenaka et al, 1995;Xiong et al, 2002;Nezasa et al, 2006;Zamek-Gliszczynski et al, 2006b,c Please note that f e, B/L values for basolateral transporters pumping directly into perfusate were calculated using eq. 4.2, whereas f e, B/L for canalicular transporters pumping in the opposite direction (into the bile) were calculated using eq.…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Relationship between Drug/Metabolite Exposure and Impairment of Excretory Transport Function

Zamek‐Gliszczynski

Kalvass²,

Pollack³

et al. 2008

Drug Metab Dispos

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ABSTRACT:The quantitative impact of excretory transport modulation on the systemic exposure to xenobiotics and derived metabolites is poorly understood. This article presents fundamental relationships between exposure and loss of a specific excretory process that contributes to overall clearance. The mathematical relationships presented herein were explored on the basis of hepatic excretory data for polar metabolites formed in the livers of various transporter-deficient rodents. Experimental data and theoretical relationships indicated that the fold change in exposure is governed by the relationship, 1/(1 ؊ f e ), where f e is the fraction excreted by a particular transport protein. Loss of function of a transport pathway associated with f e < 0.5 will have minor consequences (<2-fold) on exposure, but exposure will increase exponentially in response to loss of function of transport pathways with f e > 0.5. These mathematical relationships may be extended to other organs, such as the intestine and kidney, as well as to systemic drug exposure. Finally, the relationship between exposure and f e is not only applicable to complete loss of function of a transport pathway but also can be extended to partial inhibition scenarios by modifying the equation with the ratio of the inhibitor concentration and inhibition constant.Quantitative methods to predict the change in drug exposure resulting from drug-drug interactions occurring at the level of excretory transport have not been fully developed. A fundamental understanding of the effect of excretory transport modulation on drug/metabolite exposure is presently lacking. Kinetic approaches originally used to examine issues related to drug metabolism, such as the relative activity factor method, are now being applied to transport processes (Hirano et al., 2004). In this article, the equation describing the effect of inhibition of drug metabolism on systemic concentrations (Rowland and Matin, 1973) is adapted to explore the effect of transport modulation on exposure.Hepatobiliary excretion data for polar metabolites generated in perfused livers of various transporter-deficient animals are used primarily in this article as supporting evidence for the theoretical equations. However, the relationships presented are applicable to any organ such as the intestine and kidney in which the formed metabolites can be excreted into two distinct compartments. Most importantly, the relationship describing the fold change in exposure is applicable not only to an isolated organ but also to the systemic exposure of drugs and metabolites when systemic clearance is mediated by excretory transport. This article provides proof that the maximum fold change in exposure to a drug or metabolite cleared by active excretion is dictated by the relationship 1/(1 Ϫ f e ), where f e is the fraction of total clearance mediated by the ablated transport protein. Although the equations presented may seem to be theoretically obvious, extensive experimental proof of these relationships currently does not exist...

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Relationship between Drug/Metabolite Exposure and Impairment of Excretory Transport Function

Zamek‐Gliszczynski

Kalvass²,

Pollack³

et al. 2008

Drug Metab Dispos

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“…Two distinct naturally occurring sequence variants in the rat Abcc2 gene, either at codon 401 (GY/ TR − ) [133] or at codon 855 (EHBR) [60], lead to premature stop codons and to a lack of the Abcc2 protein from the hepatocyte canalicular membrane [13,114,133]. Recently, Abcc2-knock-out mice have been generated and characterized by several groups [18,121,177]. These Abcc2-deficient mice are apparently healthy and fertile, as are As recommended by the Human Genome Variation Society (http://www.hgvs.org/mutnomen) and by ref [26], nucleotide position +1 is the A of the ATG of the translation initiation codon in the ABCC2 cDNA sequence, "c." describes a nucleotide change in relation to the ABCC2 cDNA sequence, "p." describes a change in relation to the deduced ABCC2 protein sequence, and "X" denotes a premature stop codon b If not indicated otherwise, the diagnosis of Dubin-Johnson syndrome was based on the histopathology of the liver and on elevated serum levels of conjugated bilirubin c PolyPhen online tool for assessing potential effects of amino acid substitutions, http://genetics.bwh.harvard.edu/pph d Single nucleotide polymorphism database, http://www.ncbi.nlm.nih.gov/SNP; data based on NCBI dbSNP build 125, regular updates available e Identified in cell lines derived from Japanese individuals f Probably reduced ABCC2 mRNA levels due to nonsense-mediated mRNA decay [167] the Abcc2-deficient rats.…”

Section: Transcriptional and Posttranscriptional Regulation Of Abcc2mentioning

confidence: 99%

“…Today, many sequence variants in the ABCC2 gene have been identified, as described below, but only some of them cause DubinJohnson syndrome. The hereditary deficiency of ABCC2 in humans, or of Abcc2 in the mutant rats mentioned above, and the recently generated Abcc2 knock-out mouse strains [18,121,177] illustrate the key function of this apical efflux pump in the elimination of anionic conjugates from the body. It should be noted, however, that this loss of ABCC2 function is usually well tolerated and compensated by the upregulation of other membrane transporters, particularly of ABCC3 in the basolateral membrane of hepatocytes [30,82,91].…”

Section: Introductionmentioning

confidence: 99%

The apical conjugate efflux pump ABCC2 (MRP2)

Nies

Keppler

2006

Pflugers Arch - Eur J Physiol

358

255

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ABCC2 is a member of the multidrug resistance protein subfamily localized exclusively to the apical membrane domain of polarized cells, such as hepatocytes, renal proximal tubule epithelia, and intestinal epithelia. This localization supports the function of ABCC2 in the terminal excretion and detoxification of endogenous and xenobiotic organic anions, particularly in the unidirectional efflux of substances conjugated with glutathione, glucuronate, or sulfate, as exemplified by leukotriene C 4 , bilirubin glucuronosides, and some steroid sulfates. The hepatic ABCC2 pump contributes to the driving forces of bile flow. Acquired or hereditary deficiency of ABCC2, the latter known as Dubin-Johnson syndrome in humans, causes an increased concentration of bilirubin glucuronosides in blood because of their efflux from hepatocytes via the basolateral ABCC3, which compensates for the deficiency in ABCC2-mediated apical efflux. In this article we provide an overview on the molecular characteristics of ABCC2 and its expression in various tissues and species. We discuss the transcriptional and posttranscriptional regulation of ABCC2 and review approaches to the functional analysis providing information on its substrate specificity. A comprehensive list of sequence variants in the human ABCC2 gene summarizes predicted and proven functional consequences, including variants leading to Dubin-Johnson syndrome. Keywords

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