title: Hepatic uptake of atorvastatin: influence of variability in transporter expression on uptake clearance and drug-drug interactions.
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.
authors.affiliation: Department of Pharmacy, Uppsala University, Uppsala, Sweden (A.V., M.K., E.K.S., P.A.); Uppsala University Drug Optimization and Pharmaceutical Profiling Platform (UDOPP), Chemical Biology Consortium Sweden (M.K., P.A.), Uppsala, Sweden; Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, Germany (J.R.W.); Pharmacokinetics, Dynamics and Drug Metabolism, Pfizer Global Research and Development, Pfizer Inc., Groton, Connecticut (Y.L.); and Department of Surgery, Uppsala University, Uppsala, Sweden (A.N.).
authors.forename: Anna
authors.initials: A
authors.lastname: Vildhede
authors.affiliation: Department of Pharmacy, Uppsala University, Uppsala, Sweden (A.V., M.K., E.K.S., P.A.); Uppsala University Drug Optimization and Pharmaceutical Profiling Platform (UDOPP), Chemical Biology Consortium Sweden (M.K., P.A.), Uppsala, Sweden; Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, Germany (J.R.W.); Pharmacokinetics, Dynamics and Drug Metabolism, Pfizer Global Research and Development, Pfizer Inc., Groton, Connecticut (Y.L.); and Department of Surgery, Uppsala University, Uppsala, Sweden (A.N.).
authors.forename: Maria
authors.initials: M
authors.lastname: Karlgren
authors.affiliation: Department of Pharmacy, Uppsala University, Uppsala, Sweden (A.V., M.K., E.K.S., P.A.); Uppsala University Drug Optimization and Pharmaceutical Profiling Platform (UDOPP), Chemical Biology Consortium Sweden (M.K., P.A.), Uppsala, Sweden; Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, Germany (J.R.W.); Pharmacokinetics, Dynamics and Drug Metabolism, Pfizer Global Research and Development, Pfizer Inc., Groton, Connecticut (Y.L.); and Department of Surgery, Uppsala University, Uppsala, Sweden (A.N.).
authors.forename: Elin K
authors.initials: EK
authors.lastname: Svedberg
authors.affiliation: Department of Pharmacy, Uppsala University, Uppsala, Sweden (A.V., M.K., E.K.S., P.A.); Uppsala University Drug Optimization and Pharmaceutical Profiling Platform (UDOPP), Chemical Biology Consortium Sweden (M.K., P.A.), Uppsala, Sweden; Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, Germany (J.R.W.); Pharmacokinetics, Dynamics and Drug Metabolism, Pfizer Global Research and Development, Pfizer Inc., Groton, Connecticut (Y.L.); and Department of Surgery, Uppsala University, Uppsala, Sweden (A.N.).
authors.forename: Jacek R
authors.initials: JR
authors.lastname: Wisniewski
authors.affiliation: Department of Pharmacy, Uppsala University, Uppsala, Sweden (A.V., M.K., E.K.S., P.A.); Uppsala University Drug Optimization and Pharmaceutical Profiling Platform (UDOPP), Chemical Biology Consortium Sweden (M.K., P.A.), Uppsala, Sweden; Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, Germany (J.R.W.); Pharmacokinetics, Dynamics and Drug Metabolism, Pfizer Global Research and Development, Pfizer Inc., Groton, Connecticut (Y.L.); and Department of Surgery, Uppsala University, Uppsala, Sweden (A.N.).
authors.forename: Yurong
authors.initials: Y
authors.lastname: Lai
authors.affiliation: Department of Pharmacy, Uppsala University, Uppsala, Sweden (A.V., M.K., E.K.S., P.A.); Uppsala University Drug Optimization and Pharmaceutical Profiling Platform (UDOPP), Chemical Biology Consortium Sweden (M.K., P.A.), Uppsala, Sweden; Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, Germany (J.R.W.); Pharmacokinetics, Dynamics and Drug Metabolism, Pfizer Global Research and Development, Pfizer Inc., Groton, Connecticut (Y.L.); and Department of Surgery, Uppsala University, Uppsala, Sweden (A.N.).
authors.forename: Agneta
authors.initials: A
authors.lastname: Norén
authors.affiliation: Department of Pharmacy, Uppsala University, Uppsala, Sweden (A.V., M.K., E.K.S., P.A.); Uppsala University Drug Optimization and Pharmaceutical Profiling Platform (UDOPP), Chemical Biology Consortium Sweden (M.K., P.A.), Uppsala, Sweden; Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, Germany (J.R.W.); Pharmacokinetics, Dynamics and Drug Metabolism, Pfizer Global Research and Development, Pfizer Inc., Groton, Connecticut (Y.L.); and Department of Surgery, Uppsala University, Uppsala, Sweden (A.N.) per.artursson@farmaci.uu.se.
authors.forename: Per
authors.initials: P
authors.lastname: Artursson
mesh_terms: D000069059:Atorvastatin; D001483:Base Sequence; D002460:Cell Line; D002853:Chromatography, Liquid; D017931:DNA Primers; D004347:Drug Interactions; D006538:Heptanoic Acids / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000378:metabolism* / Q000494:pharmacology; D008099:Liver / Q000378:metabolism*; D011758:Pyrroles / Q000378:metabolism* / Q000494:pharmacology; D053719:Tandem Mass Spectrometry
chemical_list: D017931:DNA Primers; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011758:Pyrroles; D000069059:Atorvastatin