Abstract
Differences in the expression and function of the organic anion transporting polypeptide (OATP) transporters contribute to interindividual variability in atorvastatin clearance. However, the importance of the bile acid transporter sodium taurocholate cotransporting polypeptide (NTCP, SLC10A1) in atorvastatin uptake clearance (CLupt) is not yet clarified. To elucidate this issue, we investigated the relative contribution of NTCP, OATP1B1, OATP1B3, and OATP2B1 to atorvastatin CLupt in 12 human liver samples. The impact of inhibition on atorvastatin CLupt was also studied, using inhibitors of different isoform specificities. Expression levels of the four transport proteins were quantified by liquid chromatography tandem mass spectrometry. These data, together with atorvastatin in vitro kinetics, were used to predict the maximal transport activity (MTA) and interindividual differences in CLupt of each transporter in vivo. Subsequently, hepatic uptake impairment on coadministration of five clinically interacting drugs was predicted using in vitro inhibitory potencies. NTCP and OATP protein expression varied 3.7- to 32-fold among the 12 sample donors. The rank order in expression was OATP1B1 > OATP1B3 ≈ NTCP ≈ OATP2B1. NTCP was found to be of minor importance in atorvastatin disposition. Instead, OATP1B1 and OATP1B3 were confirmed as the major atorvastatin uptake transporters. The average contribution to atorvastatin uptake was OATP1B1 > OATP1B3 >> OATP2B1 > NTCP, although this rank order varied among individuals. The interindividual differences in transporter expression and CLupt resulted in marked differences in drug-drug interactions due to isoform-specific inhibition. We conclude that this variation should be considered in in vitro to in vivo extrapolations.
Footnotes
- Received November 29, 2013.
- Accepted May 5, 2014.
↵1 Current affiliation: Pharmaceutical Candidate Optimization, Bristol-Myers Squibb, Princeton, New Jersey.
This work was supported by the Swedish Research Council [grant approval no. 2822]; the Swedish Fund for Research without Animal Experiments; the Lars Hierta Memorial Foundation; and O.E. and Edla Johansson’s Scientific Foundation.
Part of this work was presented as follows:
Karlgren M, Vildhede A, Wisniewski J, and Artursson P (2012) Variability in OATP protein expression and influence on atorvastatin uptake and drug-drug interactions. Abstract P289. 19th International Symposium on Microsome and Drug Oxidations (MDO)/12th European Regional ISSX Meeting; 2012 June 17–21; Noordwijk aan Zee, the Netherlands. International Society for the Study of Xenobiotics, Washington, DC.
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- Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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