Interspecies scaling of biliary excreted drugs

Mahmood, Iftekhar; Sahajwalla, Chandra

doi:10.1002/jps.10174

Cited by 68 publications

(78 citation statements)

References 17 publications

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“…However, because of the lack of the purified MRP2/Mrp2 proteins as calibration standard for each species, we were not able to compare the protein level across species. In addition, the results were not consistent with the mRNA levels of MRP2/Mrp2 and also not in the agreement with the differential transport activities of MRP2/Mrp2 reported previously (Ishizuka et al, 1999;Mahmood and Sahajwalla, 2002;Shilling et al, 2006;Li et al, 2008a).…”

Section: Resultscontrasting

confidence: 85%

“…In each stage of drug discovery, accurate prediction of human pharmacokinetics for a potential drug candidate is of great value (Mahmood, 1999). Even though the interspecies scaling methods based on physiologically allometric procedures have been successfully applied, particularly into extrapolation of hepatic enzymatic metabolism and urinary excretion (Dedrick et al, 1970;Iwatsubo et al, 1997;Ito et al, 1998), the in vitro or in vivo model for biliary excretion predication is far from being mature (Mahmood and Sahajwalla, 2002). The remarkable interspecies differences in biliary excretion of xenobiotics and drugs/metabolites (Ishizuka et al, 1999;Shilling et al, 2006) may cause significant overestimation of biliary excretion in humans simply by an exponential allometric extrapolation approach (Lave et al, 1999;Pahlman et al, 1999;Ayrton and Morgan, 2001).…”

mentioning

confidence: 99%

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Absolute Difference of Hepatobiliary Transporter Multidrug Resistance-Associated Protein (MRP2/Mrp2) in Liver Tissues and Isolated Hepatocytes from Rat, Dog, Monkey, and Human

Li¹,

Zhang²,

Hua³

et al. 2008

Drug Metab Dispos

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ABSTRACT:We previously reported that hepatobiliary transporter multidrug resistance-associated protein (MRP2/Mrp2) is considered to be the major cause of the interspecies differences detected by efflux of fluorescent substrates in isolated hepatocytes. In the present study, the interspecies differences of MRP2/Mrp2 were first evaluated by quantitative real-time polymerase chain reaction and Western blotting. The mRNA levels were able to distinguish the difference among species with a rank order comparable with the corresponding activities observed, whereas the extents of the differences remained unknown. The cross-reactions of MRP2/Mrp2 protein of different species with anti-human MRP2 polyclonal antibody were found by Western blotting. However, because of the unknown binding affinity of antibody to MRP2/Mrp2 protein across species and lack of purified MRP2/Mrp2 proteins for calibration, the immunoblotting assay was excluded from the absolute quantification of MRP2/Mrp2 protein for multiple species. By using our newly developed liquid chromatography-tandem mass spectrometry quantification method, we were able to measure the absolute amount of MRP2/Mrp2 in liver tissues and isolated hepatocytes across species. Freshly isolated hepatocytes conserved MRP2/ Mrp2 protein levels that are comparable with those in the liver tissues. The amount of Mrp2 in rat liver was approximately 10-fold higher than that in other species. Moreover, a significant loss of Mrp2 protein in the membrane fraction of rat cryopreserved hepatocytes was observed. Thus, the absolute differences of MRP2/ Mrp2 levels in various species were determined, for the first time, by direct quantification. The results could potentially fill the translational gaps of in vitro/in vivo or preclinical species to human extrapolation of hepatobiliary elimination mediated by MRP2/ Mrp2.Xenobiotics and their metabolites are generally eliminated and detoxified by phase I and phase II enzymatic metabolism, by phase III transporter-mediated drug efflux to bile, or by both mechanisms. The excretion of drugs by hepatocytes into bile is one of the primary elimination routes for xenobiotics and the conjugate metabolites (Arias et al., 1993). In each stage of drug discovery, accurate prediction of human pharmacokinetics for a potential drug candidate is of great value (Mahmood, 1999). Even though the interspecies scaling methods based on physiologically allometric procedures have been successfully applied, particularly into extrapolation of hepatic enzymatic metabolism and urinary excretion (Dedrick et al., 1970;Iwatsubo et al., 1997;Ito et al., 1998), the in vitro or in vivo model for biliary excretion predication is far from being mature (Mahmood and Sahajwalla, 2002). The remarkable interspecies differences in biliary excretion of xenobiotics and drugs/metabolites (Ishizuka et al., 1999;Shilling et al., 2006) may cause significant overestimation of biliary excretion in humans simply by an exponential allometric extrapolation approach (Lave et al., 1999;Pahlman et al., ...

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Section: Resultscontrasting

confidence: 85%

mentioning

confidence: 99%

Absolute Difference of Hepatobiliary Transporter Multidrug Resistance-Associated Protein (MRP2/Mrp2) in Liver Tissues and Isolated Hepatocytes from Rat, Dog, Monkey, and Human

Li¹,

Zhang²,

Hua³

et al. 2008

Drug Metab Dispos

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“…Because no correction method has been proposed for SA with exponents greater than 1.3, the CL⅐BrW correction approach was used for cases with exponents greater than 1.3, as the CL⅐BrW correction yields a greater downward correction than the CL⅐MLP correction (Tang and Mayersohn, 2005b). During drug development (phase 0), the information on whether a compound undergoes predominantly biliary excretion in animals or humans may not be available until the compound is in late development; therefore, no subsequent correction factors such as those described by Mahmood (2005b) for biliary excretion drugs were applied as the analysis was carried out as a prospective approach.…”

Section: Methodsmentioning

confidence: 99%

Interspecies Prediction of Human Drug Clearance Based on Scaling Data from One or Two Animal Species

Tang¹,

et al. 2007

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ABSTRACT:A data-driven approach was adopted to derive new one-and twospecies-based methods for predicting human drug clearance (CL) using CL data from rat, dog, or monkey (n ‫؍‬ 102). The new onespecies methods were developed as CL human /kg ‫؍‬ 0.152 ⅐ CL rat /kg, CL human /kg ‫؍‬ 0.410 ⅐ CL dog /kg, and CL human /kg ‫؍‬ 0.407 ⅐ CL monkey / kg, referred to as the rat, dog, and monkey methods, respectively. The coefficient of the monkey method (0.407) was similar to that of the monkey liver blood flow (LBF) method (0.467), whereas the coefficients of the rat method (0.152) and dog method (0.410) were considerably different from those of the LBF methods (rat, 0.247; dog, 0.700). The new rat and dog methods appeared to perform better than the corresponding LBF methods, whereas the monkey method and the monkey LBF method showed improved predictability compared with the rat and dog one-species-based methods and the allometrically based "rule of exponents" (ROE). The new two-species methods were developed as CL human ‫؍‬ a rat-dog ⅐ W human 0.628 (referred to as rat-dog method) and CL human ‫؍‬ a rat-monkey ⅐ W human 0.650 (referred to as rat-monkey method), where a rat-dog and a rat-monkey are the coefficients obtained allometrically from the corresponding two species. The predictive performance of the two-species methods was comparable with that of the three-species-based ROE. Twenty-six Wyeth compounds having data from mouse, rat, dog, monkey, and human were used to test these methods. The results showed that the rat, dog, monkey, rat-dog, and rat-monkey methods provided improved predictions for the majority of the compounds compared with those for the ROE, suggesting that the use of three or more species in an allometrically based approach may not be necessary for the prediction of human exposure.

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“…Our laboratory is currently generating in vitro plasma protein binding and intrinsic clearance data for the compounds described here and will report separately on their influence on the overall scaling of these data. Application of these correction factors will additionally necessitate a consideration of the major route of elimination of each of these molecules (Mahmood, 1998;Mahmood and Sahajwalla, 2002). Finally, the present analysis does not consider the degree to which physicochemical properties or structural features of a given molecule may contribute to whether its clearance can be successfully extrapolated to humans from the preclinical data, or the potential use of computational approaches as replacements for or adjuncts to the preclinical data in extrapolation of clearance.…”

Section: Ward and Smithmentioning

confidence: 99%

A Comprehensive Quantitative and Qualitative Evaluation of Extrapolation of Intravenous Pharmacokinetic Parameters From Rat, Dog, and Monkey to Humans. I. Clearance

Ward¹,

Smith²

2004

Drug Metab Dispos

188

195

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ABSTRACT:This study was conducted to comprehensively survey the available literature on intravenous pharmacokinetic parameters in the rat, dog, monkey, and human, and to compare common methods for extrapolation of clearance, to identify the most appropriate species to use in pharmacokinetic lead optimization, and to ascertain whether adequate prospective measures of predictive success are currently available. One hundred three nonpeptide xenobiotics were identified with intravenous pharmacokinetic data in rat, dog, monkey, and human; both body weight-and hepatic blood flowbased methods were used for scaling of clearance. Allometric scaling approaches, particularly those using data from only two of the preclinical species, were less successful at predicting human clearance than methods based on clearance as a set fraction of liver blood flow from an individual species. Furthermore, commonly used prospective measures of allometric scaling success, including correlation coefficient and allometric exponent, failed to discriminate between successful and failed allometric predictions. In all instances, the monkey tended to provide the most qualitatively and quantitatively accurate predictions of human clearance and also afforded the least biased predictions compared with other species. Additionally, the availability of data from both common nonrodent species (dog and monkey) did not ensure enhanced predictive quality compared with having only monkey data. The observations in this investigation have major implications for pharmacokinetic lead optimization and for prediction of human clearance from in vivo preclinical data and support the continued use of nonhuman primates in preclinical pharmacokinetics.

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Interspecies scaling of biliary excreted drugs

Cited by 68 publications

References 17 publications

Absolute Difference of Hepatobiliary Transporter Multidrug Resistance-Associated Protein (MRP2/Mrp2) in Liver Tissues and Isolated Hepatocytes from Rat, Dog, Monkey, and Human

Absolute Difference of Hepatobiliary Transporter Multidrug Resistance-Associated Protein (MRP2/Mrp2) in Liver Tissues and Isolated Hepatocytes from Rat, Dog, Monkey, and Human

Interspecies Prediction of Human Drug Clearance Based on Scaling Data from One or Two Animal Species

A Comprehensive Quantitative and Qualitative Evaluation of Extrapolation of Intravenous Pharmacokinetic Parameters From Rat, Dog, and Monkey to Humans. I. Clearance

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