2017 MARCH

Quantification of drug concentrations

Drugs that enter into hepatocytes by passive diffusion generate concentrations that should not exceed plasma concentrations. Uptake and efflux transporters generate drug concentration gradients between plasma and hepatocytes (also designed as Kpuu) as well as between hepatocytes and bile canaliculi. Quantification of drug concentrations is important because high hepatocyte concentrations may induce cell toxicity while low hepatocyte concentrations may impair efficiency when targets are located inside hepatocytes. The following table highlights the characteristics of methods that quantify drug concentrations. In vivo liver imaging is informative but the information remains incomplete. Ex-vivo liver studies (perfused livers) are important because they conserve the organ architecture but results cannot be directly extrapolated to humans. Nevertheless, the model is important for the mechanistic understanding of hepatocyte concentrations. Recent publications highlight unbound drug concentrations in hepatocytes as well as how pharmacokinetic modelling can determine these concentrations. Related topics include the understanding of: 1) concentrations at target sites; 2) how transporters modify drug concentrations around metabolic enzymes and prolong or shorten enzyme activities; and 3) concentration gradients between cytosol and organelles.

Concentrations quantified by in vivo imaging

  • Bioorg Med Chem. 2017;25(3):963-976. Design, synthesis, in vitro characterization and preliminary imaging studies on fluorinated bile acid derivatives as PET tracers to study hepatic transporters. Testa A, Dall'Angelo S, Mingarelli M, Augello A, Schweiger L, Welch A, Elmore CS, Sharma P, Zanda M. PubMed
  • J Clin Pharmacol. 2016;56 Suppl 7:S143-56. Use of PET imaging to evaluate transporter-mediated drug-drug interactions. Langer O. PubMed
  • Drug Metab Dispos. 2015;43:1795-804. Modulation of P-glycoprotein at the human blood-brain barrier by quinidine or rifampin treatment: a Positron Emission Tomography imaging study. Liu L, Collier AC, Link JM, Domino KB, Mankoff DA, Eary JF, Spiekerman CF, Hsiao P, Deo AK, Unadkat JD. PubMed
  • Mol Pharm. 2015;12:3214-25. Factors governing P-Glycoprotein-mediated drug-drug interactions at the blood-brain barrier measured with Positron Emission Tomography. Wanek T, Römermann K, Mairinger S, Stanek J, Sauberer M, Filip T, Traxl A, Kuntner C, Pahnke J, Bauer F, Erker T, Löscher W, Müller M, Langer O. PubMed
  • Mol Pharm. 2015;12:2203-16. PET tracers to study clinically relevant hepatic transporters. Testa A, Zanda M, Elmore C, Sharma. PubMed

Ex vivo livers

  • Eur J Drug Metab Pharmacokinet. 2016; in press. Liver perfusion modifies Gd-DTPA and Gd-BOPTA hepatocyte concentrations through transfer clearances across sinusoidal membranes. Daire JL, Leporq B, Vilgrain V, Van Beers BE, Schmidt S, Pastor CM. PubMed
  • Contrast Media Mol Imaging. 2016;11:291-8. How transfer rates generate Gd-BOPTA concentrations in rat liver compartments: implications for clinical liver imaging with hepatobiliary contrast agents. Pastor CM. PubMed
  • Int J Mol Sci. 2014;16:135-47. Quantification of drug transport function across the multiple resistance-associated protein 2 (Mrp2) in rat livers. Bonnaventure P, Pastor CM. Concentration gradients between bile canaliculi and hepatocytes characterise canalicular transporter function. PubMed

Intracellular unbound concentrations and liver to plasma concentration gradients (Kpuu)

  • Sci Rep. 2017;7:43047. Intracellular drug bioavailability: a new predictor of system dependent drug disposition. Mateus A, Treyer A, Wegler C, Karlgren M, Matsson P, Artursson P. PubMed
  • Drug Metab Dispos. 2017; in press. Novel method to predict in vivo liver-to-plasma Kpuu for OATP substrates using suspension hepatocytes. Riccardi K, Lin J, Li Z, Niosi M, Ryu S, Hua W, Atkinson K, Kosa RE, Litchfield J, Di L. PubMed
  • Drug Metab Dispos. 2017; in press. Assessing the risk of drug-induced cholestasis using unbound intrahepatic concentrations. Riede J, Poller B, Huwyler J, Camenisch G. PubMed
  • Drug Metab Dispos. 2016;44:356-64. Rapid method to determine intracellular drug concentrations in cellular uptake assays: application to metformin in Organic Cation Transporter 1-transfected Human Embryonic Kidney 293 Cells. Chien HC, Zur AA, Maurer TS, Yee SW, Tolsma J, Jasper P, Scott DO, Giacomini KM. PubMed
  • Drug Metab Dispos. 2016;44:1633-42. Determination of unbound partition coefficient and in vitro-in vivo extrapolation for SLC13A transporter-mediated uptake. Riccardi K, Li Z, Brown JA, Gorgoglione MF, Niosi M, Gosset J, Huard K, Erion DM, Di L. PubMed
  • J Pharm Sci. 2015;104:2378-87. Unbound ritonavir concentrations in rat and human hepatocytes. Keemink J, Augustijns P, Annaert P. PubMed
  • Annu Rev Pharmacol Toxicol. 2014;54:509-35. Role of hepatic efflux transporters in regulating systemic and hepatocyte exposure to xenobiotics. Pfeifer ND1, Hardwick RN, Brouwer KL. PubMed
  • Mol Pharm. 2013;10:2467-78. Rapid measurement of intracellular unbound drug concentrations. Mateus A, Matsson P, Artursson P. PubMed
  • Drug Metab Dispos. 2013;41:1949-56. Determination of intracellular unbound concentrations and subcellular localization of drugs in rat sandwich-cultured hepatocytes compared with liver tissue. Pfeifer ND, Harris KB, Yan GZ, Brouwer KL. PubMed
  • Clin Pharmacol Ther. 2013;94:126-41. Intracellular drug concentrations and transporters: measurement, modeling, and implications for the liver. Chu X, Korzekwa K, Elsby R, Fenner K, Galetin A, Lai Y, Matsson P, Moss A, Nagar S, Rosania GR, Bai JP, Polli JW, Sugiyama Y, Brouwer KL; International Transporter Consortium. PubMed
  • Clin Pharmacol Ther. 2013;93:263-6. Intracellular drug concentrations. Dollery CT. PubMed

Pharmacokinetic modelling and hepatocyte concentrations

  • J Pharmacol Exp Ther. 2016;359:26-36. Intracellular unbound atorvastatin concentrations in the presence of metabolism and transport. Kulkarni P, Korzekwa K, Nagar S. PubMed
  • Drug Metab Dispos. 2012;40(5):865-76. Models to predict unbound intracellular drug concentrations in the presence of transporters. Korzekwa KR, Nagar S, Tucker J, Weiskircher EA, Bhoopathy S, Hidalgo IJ. PubMed