2016 SEPTEMBER

The topic of the month focuses on transporter-mediated drug-drug interactions evidenced by liver imaging. Images assess the mean drug concentrations inside regions of interest. True concentrations in hepatocytes are then impossible to measure by imaging. For information, I show in a recent publication PubMed how transfer rates across hepatocyte membranes generate Gd-BOPTA concentrations in each rat liver compartment. Translation to clinical liver imaging with hepatobiliary contrast agents is highlighted. Oliver Langer published several recent articles on the subject with PET imaging. Kim Brouwer and Yuichi Sugiyama also added important information.

From members of the network

  • J Clin Pharmacol. 2016;56:S143-56. Use of PET imaging to evaluate transporter-mediated drug-drug interactions. Langer O. PubMed
  • Basic Clin Pharmacol Toxicol. 2016; in press. Hepatocyte concentrations of indocyanin green (ICG) reflect transfer rates across membrane transporters. Cusin F, Azevedo LF, Bonnaventure P, Desmeules J, Daali Y, Pastor CM. PubMed
  • Clin Pharmacol Ther. 2014;96:206-13. Using positron emission tomography to study transporter-mediated drug-drug interactions in tissues. Wulkersdorfer B, Wanek T, Bauer M, Zeitlinger M, Müller M, Langer O. PubMed
  • CPT Pharmacometrics Syst Pharmacol. 2013;2:e20. Effect of ritonavir on (99m)Technetium-mebrofenin disposition in humans: A semi-PBPK modeling and in vitro approach to predict transporter-mediated DDIs. Pfeifer ND, Goss SL, Swift B, Ghibellini G, Ivanovic M, Heizer WD, Gangarosa LM, Brouwer KL. PubMed
  • Drug Metab Dispos. 2013;41:1548-56. Evidence of drug-drug interactions through uptake and efflux transport systems in rat hepatocytes: implications for cellular concentrations of competing drugs. Daali Y, Millet P, Dayer P, Pastor CM. PubMed
  • Bioorg Med Chem. 2013;21:7584-90. The synthesis and biodistribution of [(11)C]metformin as a PET probe to study hepatobiliary transport mediated by the multi-drug and toxin extrusion transporter 1 (MATE1) in vivo. Hume WE, Shingaki T, Takashima T, Hashizume Y, Okauchi T, Katayama Y, Hayashinaka E, Wada Y, Kusuhara H, Sugiyama Y, Watanabe Y. PubMed
  • J Nucl Med. 2012;53:741-8. PET imaging-based evaluation of hepatobiliary transport in humans with (15R)-11C-TIC-Me. Takashima T, Kitamura S, Wada Y, Tanaka M, Shigihara Y, Ishii H, Ijuin R, Shiomi S, Nakae T, Watanabe Y, Cui Y, Doi H, Suzuki M, Maeda K, Kusuhara H, Sugiyama Y, Watanabe Y. PubMed
  • Radiology. 2003;229:119-25.  Kinetics of gadobenate dimeglumine in isolated perfused rat liver: MR imaging evaluation. Pastor CM, Planchamp C, Pochon S, Lorusso V, Montet X, Mayer J, Terrier F, Vallée JP. PubMed. Bromosulphophtalein inhibits Gd-BOPTA entry into hepatocytes.

From other research groups

  • Nucl Med Biol. 2016;43:642-649. Synthesis, in vitro and in vivo small-animal SPECT evaluation of novel technetium labeled bile acid analogues to study (altered) hepatic transporter function. Neyt S, Vliegen M, Verreet B, De Lombaerde S, Braeckman K, Vanhove C, Huisman MT, Dumolyn C, Kersemans K, Hulpia F, Van Calenbergh S, Mannens G, De Vos F. PubMed
  • Mol Pharm. 2015;12:2203-16. PET tracers to study clinically relevant hepatic transporters. Testa A, Zanda M, Elmore CS, Sharma P. PubMed
  • Jpn J Radiol. 2013;31:386-92. Effect of lapatinib on hepatic parenchymal enhancement on gadoxetate disodium (EOB)-enhanced MRI scans of the rat liver. Nakamura Y, Hirokawa Y, Kitamura S, Yamasaki W, Arihiro K, Tatsugami F, Iida M, Kakizawa H, Date S, Awai K. PubMed
  • NMR Biomed. 2013;26:1258-70. Assessment of gadoxetate DCE-MRI as a biomarker of hepatobiliary transporter inhibition. Ulloa JL, Stahl S, Yates J, Woodhouse N, Kenna JG, Jones HB, Waterton JC, Hockings PD. PubMed
  • Toxicol Appl Pharmacol. 2012;263:244-50. Application of quantitative time-lapse imaging (QTLI) for evaluation of Mrp2-based drug-drug interaction induced by liver metabolites. Nakanishi T, Ikenaga M, Fukuda H, Matsunaga N, Tamai I. PubMed
  • Drug Metab Dispos. 2011;39:984-91. Quantitative time-lapse imaging-based analysis of drug-drug interaction mediated by hepatobiliary transporter, multidrug resistance-associated protein 2, in sandwich-cultured rat hepatocytes. Nakanishi T, Shibue Y, Fukuyama Y, Yoshida K, Fukuda H, Shirasaka Y, Tamai I. PubMed
  • J Magn Reson Imaging. 2011;33:409-16. Evaluation of possible drug-drug interaction between gadoxetic acid and erythromycin as an inhibitor of organic anion transporting peptides (OATP). Huppertz A, Breuer J, Fels LM, Schultze-Mosgau M, Sutter G, Klein S, Frericks B, Hamm B, Wagner M. PubMed
  • Drug Discov Today. 2007;12:833-7. Drug-drug interactions affected by the transporter protein, P-glycoprotein (ABCB1, MDR1) I. Preclinical aspects. Aszalos A. PubMed