title: Species differences in biliary clearance and possible relevance of hepatic uptake and efflux transporters involvement.
abstract: From a search of the available literature, a database of 22 drugs of all charge types and several different therapeutic classes was compiled to compare rat and human biliary clearance data. Dog biliary excretion data were also found for nine of the drugs. For 19 of the 22 drugs (86%), rat unbound biliary clearance values, when normalized for body weight, exceeded those for humans by factors ranging from 9 to over 2500-fold, whereas human/dog differences were much less dramatic. It was possible to define hepatic uptake and efflux transporter involvement for many of the drugs. On the basis of the findings, it is postulated that regardless of the biliary efflux transporters implicated, when drugs do not require active hepatic uptake to access the liver there may be fairly insignificant differences in rat, dog, and human biliary clearance. Conversely, when the organic anion-transporting polypeptide drug transporters are involved, one may expect at least a 10-fold discrepancy in rat to human biliary clearance normalized for body weight and corrected for plasma protein binding.
authors.affiliation: Respiratory and Inflammation Drug Metabolism and Pharmacokinetics, Astra Zeneca R&D, Mölndal, Sweden. ken.grime@astrazeneca.com
authors.forename: Ken
authors.initials: K
authors.lastname: Grime
authors.forename: Stuart W
authors.initials: SW
authors.lastname: Paine
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000818:Animals; D001646:Bile / Q000378:metabolism*; D001835:Body Weight; D004285:Dogs; D004333:Drug Administration Routes; D006801:Humans; D008099:Liver / Q000378:metabolism*; D026901:Membrane Transport Proteins / Q000378:metabolism*; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism; D027361:Organic Anion Transporters / Q000378:metabolism; D004364:Pharmaceutical Preparations / Q000008:administration & dosage / Q000378:metabolism*; D011485:Protein Binding; D051381:Rats; D013045:Species Specificity
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D026901:Membrane Transport Proteins; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; D027361:Organic Anion Transporters; D004364:Pharmaceutical Preparations; C116614:ABCG2 protein, human; C489249:Abcg2 protein, rat