Abstract
Although the dog is frequently used in pharmacological, pharmacokinetic and drug safety studies, little is known about canine drug transporters. Dog Oatp1b4 has recently been cloned (Gui and Hagenbuch, 2010), but the contribution of Oatp1b4 to hepatic uptake has yet to be clarified. This study compares the transport characteristics of dog Oatp1b4 to that 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 thirty times that 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 tested compounds were transported by Oatp1b4 and uptake clearance (CLint,uptake) in dog hepatocytes in sodium-free buffer was correlated significantly with CLint,uptake in Oatp1b4-expressing cells. Dog in vivo clearance for five substrates was predicted more accurately from CLint,uptake rather than CLint,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 that of human OATP1B1/OATP1B3, while the relative uptake clearance of substrates for Oatp1b4 correlate better with OATP1B3 than the more abundant hepatic analogue OATP1B1.
- active transport
- drug transport
- hepatic transport
- hepatic uptake
- hepatobiliary transport
- hepatocytes
- in vitro-in vivo prediction
- isolated hepatocytes
- organic anion transport
- transporters
- Received July 15, 2011.
- Accepted September 22, 2011.
- The American Society for Pharmacology and Experimental Therapeutics