Hepatobiliary disposition of rhodamine 123 in isolated perfused rat livers

Parasrampuria, Ridhi; Mehvar, Reza

doi:10.1080/00498250802411421

Cited by 10 publications

(17 citation statements)

References 12 publications

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“…The apparent biliary clearance (A) and BEI (B) of RH-123 and CL bile,app of RH-Glu (C) are presented in Figure 5. The BEI values could not be estimated for RH-Glu because, in agreement with a previous report (12), no RH-Glu was detected in the liver. Both CL bile,app ( Figure 5A) and BEI ( Figure 5B) values of RH-123 in the IR-24 group were substantially lower than the corresponding values in the Sham-24 group.…”

Section: Resultsmentioning

confidence: 50%

“…The apparent biliary clearance (CL bile,app ) of RH-123 or its generated metabolite RH-Glu were estimated by dividing the total amount of the drug or the metabolite excreted into the bile during the 60 min of perfusion by its respective perfusate AUC during the same period. Because of continuous accumulation and sequestration of RH-123 in the liver tissue during the constant infusion of RH-123 in IPRLs despite pseudo-steady state perfusate concentrations, the CL bile,app of RH-123 is expected to increase with an increase in the length of perfusion (12). Therefore, another parameter, termed biliary excretion index (BEI), was also calculated for RH-123 as shown in the following equation:…”

Section: Pharmacokinetic Analysismentioning

confidence: 99%

“…The concentrations of RH-123 and RH-110 in the liver homogenates, perfusate, and bile were analyzed by fluorescence HPLC both before and after treatment with -glucuronidase, as described by us before (12). The concentrations of RH-Glu were then determined by subtracting the RH-123 concentrations in the unhydrolyzed samples from those in the corresponding hydrolyzed samples.…”

Section: Sample Analysismentioning

confidence: 99%

“…_________________________________________ The cationic dye rhodamine 123 (RH-123) is a P-gp substrate, which has been used extensively as a marker of P-gp activity in vitro in cells, ex vivo in isolated organs, and in vivo in whole animals. We have recently (12) characterized the hepatobiliary disposition of RH-123 in an isolated perfused liver (IPRL) model and showed that the biliary excretion of the dye is reduced after pharmacological inhibition of P-gp activity (13). Additionally, it was shown that the biliary clearance of the glucuronidated metabolite of the dye (RH-Glu) is sensitive to the modulation of Mrp2 activity (13).…”

Section: Introductionmentioning

confidence: 99%

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Effects of In Vivo Hepatic Ischemia-Reperfusion Injury on the Hepatobiliary Disposition of Rhodamine 123 and its Metabolites in Isolated Perfused Rat Livers

2012

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-Purpose.A few studies have shown that normothermic hepatic ischemia-reperfusion (IR) injury may affect the mRNA and/or protein levels of canalicular transporters P-glycoprotein (P-gp) and multidrug resistance-associated protein 2 (Mrp2). However, the effects of the injury on the functions of these canalicular transporters with respect to the biliary excretion of drugs remain largely unknown. Therefore, the purpose of this study was to investigate the effects of warm hepatic IR on the hepatobiliary disposition of rhodamine 123 (RH-123), a P-gp substrate, and its glucuronidated metabolite (RH-Glu), an Mrp2 substrate, in rats. Methods. Twenty four or 72 h following a 60-min partial ischemia or sham operation in rats, livers were isolated and perfused ex vivo with a constant concentration (~100 ng/mL) of RH-123. The concentration of RH-123 and its glucuronidated (RH-Glu) and deacylated (RH-110) metabolites were determined in the outlet perfusate, bile, and the liver tissue using HPLC, and relevant pharmacokinetic parameters were estimated. Results. Twentyfour-h IR caused a significant reduction in the hepatic extraction ratio of RH-123 (IR: 0.857 ± 0.078; Sham: 0.980 ± 0.017) and the biliary recovery of the parent drug and RH-Glu by 43% and 44%, respectively. The reductions in the biliary recovery were associated with significant reductions in the apparent biliary clearance of RH-123 and RH-Glu. Mass balance data showed that the formation of the glucuronidated or deacylated metabolite was not significantly affected by the 24-h IR injury. In contrast to the 24-h IR, the injury did not have any effect on the hepatobiliary disposition of RH-123 or its metabolites following 72 h of reperfusion. Conclusions. It is concluded that the pharmacokinetics of drugs that are subject to biliary excretion by the canalicular P-gp and Mrp2 transporters may be altered shortly after hepatic IR injury.

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Section: Resultsmentioning

confidence: 50%

Section: Pharmacokinetic Analysismentioning

confidence: 99%

Section: Sample Analysismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Effects of In Vivo Hepatic Ischemia-Reperfusion Injury on the Hepatobiliary Disposition of Rhodamine 123 and its Metabolites in Isolated Perfused Rat Livers

2012

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“…The concentrations of RH-123 and RH-110 in the liver homogenate, perfusate, and bile samples were analyzed by HPLC both before and after treatment with -glucuronidase as described by us earlier [35].…”

Section: Sample Analysismentioning

confidence: 99%

Divergent Effects of Nitric Oxide Donors on the Biliary Efflux Transporters in Isolated Perfused Rat Livers: Nitric Oxide-Independent Inhibition of ABC Transporters by Sodium Nitroprusside

Parasrampuria¹,

Mehvar²

2011

DML

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Rhodamine 123 (RH-123) and its glucuronidated metabolite (RH-Glu) are excreted into the bile via the ABC efflux transporters P-glycoprotein (P-gp) and multidrug resistance-related protein type 2 (Mrp2), respectively. In this study, we investigated the short-term (2 h) effects of a low or high concentration of nitric oxide (NO) donors sodium nitroprusside (SNP) and isosorbide dinitrate (ISDN) on the hepatobiliary disposition of RH-123 and its metabolite in an isolated perfused rat liver model. Additionally, the effects of ISDN on the hepatobiliary disposition of 5 (and 6)-carboxy-2', 7'- dichlorofluorescein (CDF), a specific marker of Mrp2, were investigated in the same model. Whereas SNP caused a substantial (85-90%) reduction in the P-gp- and Mrp2-mediated transport of RH-123 and RH-Glu, respectively, ISDN did not affect either of these transporters. However, ISDN reduced the biliary recovery of RH-Glu, most likely because of inhibition of the formation of the metabolite. Further studies showed that the effects of SNP on these transporters are due to a substantial (88%) depletion of hepatic ATP levels by this NO donor. Additionally, studies using CDF revealed an almost identical hepatobiliary disposition of this Mrp2 marker in the presence or absence of ISDN. It is concluded that short-term exposure of rat livers to NO does not affect the functions of the efflux transporters P-gp and Mrp2. The observed inhibitory effects of SNP on the functions of both P-gp and Mrp2 are via an NO-independent mechanism.

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Effects of P-glycoprotein and Mrp2 inhibitors on the hepatobiliary disposition of Rhodamine 123 and its glucuronidated metabolite in isolated perfused rat livers

Parasrampuria

Mehvar

2010

Journal of Pharmaceutical Sciences

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Hepatobiliary disposition of rhodamine 123 in isolated perfused rat livers

Cited by 10 publications

References 12 publications

Effects of In Vivo Hepatic Ischemia-Reperfusion Injury on the Hepatobiliary Disposition of Rhodamine 123 and its Metabolites in Isolated Perfused Rat Livers

Effects of In Vivo Hepatic Ischemia-Reperfusion Injury on the Hepatobiliary Disposition of Rhodamine 123 and its Metabolites in Isolated Perfused Rat Livers

Divergent Effects of Nitric Oxide Donors on the Biliary Efflux Transporters in Isolated Perfused Rat Livers: Nitric Oxide-Independent Inhibition of ABC Transporters by Sodium Nitroprusside

Effects of P-glycoprotein and Mrp2 inhibitors on the hepatobiliary disposition of Rhodamine 123 and its glucuronidated metabolite in isolated perfused rat livers

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