title: Hepatic uptake in the dog: comparison of uptake in hepatocytes and human embryonic kidney cells expressing dog organic anion-transporting polypeptide 1B4.
abstract: Although the dog is frequently used in pharmacological, pharmacokinetic, and drug safety studies, little is known about canine drug transporters. Dog organic anion-transporting polypeptide (Oatp1b4) has recently been cloned (Comp Biochem Physiol C Toxicol Pharmacol 151:393-399, 2010), but the contribution of Oatp1b4 to hepatic uptake has yet to be clarified. This study compares the transport characteristics of dog Oatp1b4 with those of human OATP1B1/1B3 and demonstrates the importance of Oatp1b4 in the uptake of anionic compounds in dog hepatocytes. Oatp1b4 is the predominant Oatp in dog liver with expression levels double and 30 times those of Oatp2b1 and Oatp1a2, respectively. Uptake of a range of typical OATP substrates by Oatp1b4-expressing HEK293 cells was compared with that in fresh dog hepatocytes. All compounds tested were transported by Oatp1b4 and uptake intrinsic clearance (CL(int, uptake)) in dog hepatocytes in sodium-free buffer was correlated significantly with CL(int, uptake) in Oatp1b4-expressing cells. Dog in vivo clearance for five substrates was predicted more accurately from CL(int, uptake) than from metabolic intrinsic clearance (CL(int, met)), indicating that uptake governs the overall in vivo hepatic clearance of these anionic compounds in dog. The substrate specificities of dog Oatp1b4 appear to be similar to those of human OATP1B1/OATP1B3, whereas the relative uptake clearance of substrates for Oatp1b4 correlate better with OATP1B3 than with the more abundant hepatic analog OATP1B1.
authors.affiliation: Department of Discovery DMPK, AstraZeneca R&D Charnwood, Loughborough, United Kingdom. alison.wilby@evotec.com
authors.forename: Alison J
authors.initials: AJ
authors.lastname: Wilby
authors.forename: Kazuya
authors.initials: K
authors.lastname: Maeda
authors.forename: Paul F
authors.initials: PF
authors.lastname: Courtney
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Debori
authors.forename: Peter J H
authors.initials: PJ
authors.lastname: Webborn
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Kitamura
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kusuhara
authors.forename: Rob J
authors.initials: RJ
authors.lastname: Riley
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Sugiyama
mesh_terms: D000818:Animals; D001483:Base Sequence; D017931:DNA Primers; D004285:Dogs; D006801:Humans; D008099:Liver / Q000166:cytology / Q000196:embryology / Q000378:metabolism*; D027361:Organic Anion Transporters / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics
chemical_list: D017931:DNA Primers; D027361:Organic Anion Transporters; D012333:RNA, Messenger