ABCC2/Abcc2 Transport Property in Different Species and its Modulation by Heterogeneous Factors

Abstract

ABCC2/Abcc2 is a member of the ABC transporter family expressed mainly in the liver bile canalicular membrane and involved in the excretion of various kinds of organic anions from hepatocytes into bile. During the drug development process, species differences in the pharmaco- and toxicokinetics of candidate drugs are a major problem. It is possible that ABCC2/Abcc2 transport activity as well as inhibitor sensitivity could lead to a number of phenomena (e.g. a difference in the biliary excretion clearance, a delay in the elimination half-life from the circulating blood and toxic side effects on ABCC2 -mediated drug-drug interactions, such as drug-induced hyperbilirubinemia). From this point of view, it is useful to be able to predict during preclinical development if certain compounds of interest are substrates and/or modulators of ABCC2. Although an in vivo animal model or an in vitro model expressing ABCC2 are useful assay systems, these have some limitations as far as predicting the transport profile of compounds in vivo is concerned. I will present an overview of the species differences in the tissue distribution, function, and also characteristic transport properties of ABCC2/Abcc2 mainly in an in vitro experimental model.

Species-Dependent Uptake of Glycylsarcosine but Not Oseltamivir in Pichia pastoris Expressing the Rat, Mouse, and Human Intestinal Peptide Transporter PEPT1

“…For example, LLC-PK 1 cells transfected with MDR1/Mrdr1 from human, monkey, canine, rat, and mouse exhibited a 16.5-fold difference in their apparent K m values (Katoh et al, 2006). Interspecies differences were also reported for the liver efflux transporters MRP/Mrp (Ito, 2008;Li et al, 2008) and BCRP/Bcrp (Li et al, 2008) and for the bile salt export pump BSEP/Bsep (Yabuuchi et al, 2008). However, there is sparse information on potential species differences in PEPT1-mediated transport, especially when studied in the same experimental system.…”

The limitations of renal epithelial cell line HK-2 as a model of drug transporter expression and function in the proximal tubule

“…However, these animal-derived cell lines show substantial variation in transporter expression compared to human tissue [17]. A mechanistic understanding of renal xenobiotic transport requires the development and characterisation of a realistic in vitro model of the human proximal tubule.…”

Species Differences in Human and Rodent PEPT2-Mediated Transport of Glycylsarcosine and Cefadroxil in Pichia Pastoris Transformants

“…Subsequent in situ perfusion studies in jejunum confirmed this species difference and reported 2-to 4-fold higher affinities (i.e., lower K m values) for both GlySar and cefadroxil in humanized PEPT1 mice compared with wildtype mice (Hu et al, 2014;Hu and Smith, 2016). Such observations, along with significant examples involving species-dependent pharmacokinetic profiles of other transporters, such as P-glycoprotein, MRP1, and BCRP (Katoh et al, 2006;Ito, 2008;Li et al, 2008;Chu et al, 2013), demand that transporter studies be performed in different species during drug discovery and preclinical and clinical development.…”