Contribution of Quantitative Whole-Body Autoradioluminography to the Early Selection and Development of Drug Candidates

Chapter

Abstract

Whole body autoradioluminography (WBA) utilizes radiolabeled compounds to assess the in situ tissue distribution of new chemical entities in laboratory animals and can be used to project dosimetry calculations in humans. The estimate of the tissue concentrations of radioactivity, along with the tissue distribution of radioactivity, allows for physiological-based pharmacokinetic–pharmacodynamic modeling and estimation of tissue half-life. This chapter provides a review of QWBA methods, methods, data interpretation, and applications to early drug development.

Keywords

Retina Flare Dehydration Histamine Cyclone 

References

  1. Ahmed, A.E., Jacob, S., Soliman, S., Ahmed, N., Osman, K., Loh, J.P., and Romero, N. Whole-body autoradiographic disposition, elimination and placental transport of [14C]tri-o-cresyl phosphate in mice. J. Appl. Toxicol. 1993; 13(4):259–267.PubMedCrossRefGoogle Scholar
  2. Akel, G., Benard, P., Canal, P., and Soula, G. Distribution and tumor penetration properties of a radiosensitizer 2-[14C]misonidazole (Ro 07-0582) in mice and rats as studied by whole-body autoradiography. Cancer Chemother. Pharmacol. 1986; 17:121–126.PubMedCrossRefGoogle Scholar
  3. Bake, S., and Sohrabji, F. 17beta-estradiol differentially regulates blood-brain barrier permeability in young and aging female rats. Endocrinology 2004; 145(12):5471–5475.PubMedCrossRefGoogle Scholar
  4. Bascands, J.L., and Schanstra, J.P. Obstructive nephropathy: Insights from genetically engineered animals. Kidney Int. 2005; 68:925–937.PubMedCrossRefGoogle Scholar
  5. Botta, L., Gerber, H.U., and Schmid, K. Measurement of radioactivity in biological experiments. In: Garrett, E.R. and Hirtz, J.L. (Eds), Drug, Fate and Metabolism – Methods and Techniques, Marcel Dekker, Inc., New York and Basel, 1985; vol. 5: pp. 99–134.Google Scholar
  6. Bruin, G., Faller, T., Wiegand, H., Schweitzer, A., Nick, H., Schneider, J., Boernsen, K.-O., and Waldmeier, F. Pharmacokinetics, distribution, metabolism, and excretion of deferasinox and its iron complex in rats. Drug Metab. Dispos. 2008; 36:2523–2538.PubMedCrossRefGoogle Scholar
  7. Busch, U. Whole-body autoradiography (WBAR): Use for pilot studies of pharmacokinetics in rats. Br. J. Clin. Toxicol. 1977; 41(Suppl. 1):28–29.Google Scholar
  8. Caprioli, R.M., Farmer, T.B., and Gile, J. Molecular imaging of biological samples: Localization of peptides and proteins using MALDI-TOF MS. Anal. Chem. 1997; 69:4751–4760.PubMedCrossRefGoogle Scholar
  9. Docherty, N.G., O’Sullivan, O.E., Healy, D.A., Fitzpatrick, J.M., and Watson, R.W.G. Evidence that inhibition of tubular cell apoptosis protects against renal damage and development of fibrosis following ureteric obstruction. Am. J. Physiol. Renal Physiol. 2006; 290:F4–F13.PubMedCrossRefGoogle Scholar
  10. Fand, I., Sharkey, R.M., and Goldenberg, D.M. Use of whole-body autoradiography in cancer targeting with radiolabeled antibodies. Cancer Res. 1990; 50:885s–891s.PubMedGoogle Scholar
  11. Foster, C., Howard, L., Schweitzer, A., Persohn, E., Hiestand, P., Balatoni, B., Reuschel, R., Beerli, C., Schwartz, M., and Billich, A. Brain penetration of the oral iimmunomodulatory drug FTY720 and its phosphorylation in the central nervous system during experimental autoimmune encephalomyelitis: Conse-quences for mode of action in multiple sclerosis. J. Pharmacol. Exp. Ther. 2007; 323:469–476.PubMedCrossRefGoogle Scholar
  12. Gulati, A., Dhawan, K.N., Shukla, R., Srimal, R.C., and Dhawan, B.N. Evidence for the involvement of histamine in the regulation of blood-brain barrier permeability. Pharmacol. Res. Commun. 1985; 17(4):395–404.PubMedCrossRefGoogle Scholar
  13. Hahn, E.J. Autoradiography: A review of basic principles. Am. Lab. 1983; 15(7):64–71.Google Scholar
  14. Hamaoka, T. Autoradiography of new era replacing traditional X-ray film. Cell Technol. 1990; 9:456–462.Google Scholar
  15. Hemauer, S.J., Yan, R., Patrikeeva, S.L., Mattison, D.R., Hankins, G.D., Ahmed, M.S., and Nanovskaya, T.N. Transplacental transfer and metabolism of 17-alpha-hydroxyprogesterone caproate. Am J Obstet Gynecol. 2008; 199(2):169.PubMedCrossRefGoogle Scholar
  16. Hiesiger E.M., Voorhies R.M., Basler G.A., Lipschutz L.E., Posner J.B., and Shapiro W.R. Opening the blood-brain and blood-tumor barriers in experimental rat brain tumors: The effect of intracarotid hyperosmolar mannitol on capillary permeability and blood flow. Ann. Neurol. 1986; 19(1):50–59.PubMedCrossRefGoogle Scholar
  17. Ito, T., and Brill, A.B. Variation in thickness of the large cryosections cut for whole-body autoradiography. Appl. Radiat. Isot. 1991; 42(2):187–192.CrossRefGoogle Scholar
  18. Liss, R.H. In: Mehlman, M.A., Shapiro, R.E., and Blumenthal, H. (Eds), Advances in Modern Toxicology: New Concepts in Safety Evaluation Hemisphere, Washington, DC, 1976; vol. 1: pp. 273–305.Google Scholar
  19. Luckey, G. US patent # 3, 859, 527, 1975.Google Scholar
  20. Mayhan W.G., Faraci F.M., and Heistad D.D. Effects of vasodilatation and acidosis on the blood-brain barrier. Microvasc. Res. 1988; 35(2):179–192.PubMedCrossRefGoogle Scholar
  21. Miyahara, J. The imaging plate: A new radiation image sensor. Chem. Today 1989; 223:29–36.Google Scholar
  22. Pass, D., and Freeth, G. The rat. ANZCCART News 1993; 6:4, Insert.Google Scholar
  23. Pierson, J., Norris, J.L., Aerni, H.R., Svenningsson, P., Caprioli, R.M., and Andren, P.E. Molecular profiling of experimental parkinson’s disease: Direct analysis of peptides and proteins on brain tissue sections by MALDI mass spectrometry. J. Proteome Res. 2004; 3:289–295.PubMedCrossRefGoogle Scholar
  24. Potchoiba, M.J., and Nocerini, M.R. Utility of whole-body autoradiography in drug discovery for the quantification of tritium-labeled drug candidates. Drug Metab. Dispos. 2004; 32(10):1190–1198.PubMedGoogle Scholar
  25. Potchoiba, M.G., Tensfeldt, T.G., Nocerini, M.R., and Silber, B.M. A novel quantitative method for determining the biodistribution of radiolabeled xenobiotics using whole-body cryosectioning. J. Pharmacol. Exp. Ther. 1995; 272(2):953–962.PubMedGoogle Scholar
  26. Rico, A., Benard, P., Braun, J.P., and Burgat-Sacaze, V. Application of macroscopic autoradiography to large animals in veterinary pharmacokinetics: The distribution of sodium selenite labelled with 75Se in the pig. Ann. Rech. Vét. 1978; 9(1):25–32.PubMedGoogle Scholar
  27. Rohner, T.C., Staab, D., and Stoeckli, M. MALDI mass spectrometric imaging of biological tissue sections. Mech. Ageing Dev. 2005; 126:177–185.PubMedCrossRefGoogle Scholar
  28. Sampson, D.A., and Jansen, G.R. Measurement of milk yield in the lactating rat from pup weight and weight gain. J. Pediatr. Gastroenterol. Nutr. 1984; 3(4):613–617.PubMedCrossRefGoogle Scholar
  29. Schweitzer, A. Spatial imaging of radioactivity in animal tissues and organs. In: Welling, P. (Ed.), Pharmacokinetics: Regulatory-Industrial-Academic Perspectives, 2nd edition, Marcel Dekker Inc., New York; 1995.Google Scholar
  30. Schweitzer, A., Fahr, A., and Niederberger, W. A simple method for quantitation of 14C-whole-body autoradiograms. Appl. Radiat. Isot. 1987; 38(5):329–333.CrossRefGoogle Scholar
  31. Schweitzer, A., and Englert, D. Contribution of electronic autoradiography to the assessment of the site specific delivery of radiolabelled agents. Q. J. Nucl. Med. 1995; 42–44.Google Scholar
  32. Schweitzer, A., Hasler-Nguyen, N., and Zijlstra, J. Preferential uptake of the non steroid anti-inflammatory drug diclofenac into inflamed tissues after a single oral dose in rats. BMC Pharmacol. 2009; 9:5.PubMedCrossRefGoogle Scholar
  33. Shigematsu, A. “Bao-Bei,” or the powerful technology, in science of whole-body metabolism. Autoradioluminography. Radioluminography 1992; 1(3):115.Google Scholar
  34. Shigematsu, A., Motoji, N., Hatori, A., and Satoh, T. Progressive application of autoradiography in pharmaceutical and metabolic studies for development of new drugs. Regul. Toxicol. Pharmacol. 1995; 22:122–142.PubMedCrossRefGoogle Scholar
  35. Shionoya, S. Mechanistic approach toward photostimulated luminography. Radioluminography 1992; 1(1):115.Google Scholar
  36. Solon, E., and Kraus, L. Quantitative whole-body autoradiography in the pharmaceutical. Survey results on study design, methods and regulatory compliance. J. Pharmacol. Toxicol. Meth. 2002; 43:73–81.Google Scholar
  37. Solon, E., Balani, S.K., and Lee, F.W. Whole-body autoradiography in drug discovery. Curr. Drug Metab. 2002; 3:451–462.PubMedCrossRefGoogle Scholar
  38. Stoeckli, M., Staab, D., and Schweitzer, A. Compound and metabolite distribution measured by MALDI mass spectrometric imaging in whole-body tissue sections. Int. J. Mass Spect. 2007; 260(2–3):195–202.CrossRefGoogle Scholar
  39. Stoeckli, M., Staab, D., Schweitzer, A., Gardiner, J., and Seebach, D. Imaging of a β-peptide distribution in whole-body mice sections by MALDI mass spectrometry. J. Am. Soc. Mass Spectrom. 2007; 18:1921–1924.PubMedCrossRefGoogle Scholar
  40. Tanaka, M., Takashina, H., and Tsutsumi, S. Comparative assessment of ocular tissue distribution of drug-related radioactivity after chronic oral administration of 14C-levofloxacin and 14C-chloroquine in pigmented rats. J. Pharm. Pharmacol. 2004; 56(8):977–983.PubMedCrossRefGoogle Scholar
  41. Todd, P.J., Schaff, T.G., Chaurand, P., and Caprioli, R.M. Organic ion imaging of biological tissue with MALDI and SIMS. J. Mass Spectrom. 2001; 36:355–369.PubMedCrossRefGoogle Scholar
  42. Ullberg, S. Studies on the distribution and fate of 35S-labeled benzylpenicillin in the body. Acta Radiol. Suppl. (Stockh) 1954; 118:1–110.Google Scholar
  43. Ullberg, S. Autoradiography in fetal pharmacology. In: Boreus, L. (Ed), Fetal Pharmacology Symposium, Raven Press, New York, 1971; pp. 55–73.Google Scholar
  44. Ullberg, S. The technique of whole-body autoradiography. Cryosectionning of large specimens. Science Tools (The LKB Instr. J.) Special Issue, 1977; 2–29.Google Scholar
  45. Ullberg, S., Sorbo, B., and Clemedson, C.J. Distribution of radioactive iron in pregnant mice studies by whole-body autoradiography. Acta Radiol. 1961; 55:145–155.PubMedCrossRefGoogle Scholar
  46. Ullberg, S., Kristoffersson, H., Flodh, H., and Hanngren, A. Placental passage and fetal accumulation of labelled vitamin B12 in the mouse. Arch. Int. Pharmacodyn. Ther. 1967; 167:431–449.PubMedGoogle Scholar
  47. Waddell, W.J. Localization and metabolism of drugs in the fetus. Fed. Proc. 1972; 31:52.PubMedGoogle Scholar
  48. Weiss, H., Pfaar, U., Schweitzer, A., Wiegand, H., Skerjanec, A., and Schran, H. Biodistribution and plasma protein binding of zoledronic acid. Drug Metab. Dispos. 2008; 36:2043–2049.PubMedCrossRefGoogle Scholar
  49. Wyss, M.T., Ametamey S.M., Treyer V., Bettio A., Blagoev M., Kessler L.J., Burger C., Weber B., Schmidt M., Gasparini F., and Buck A. Quantitative evaluation of 11C-ABP688 as PET ligand for the measurement of the metabotropic glutamate receptor subtype 5 using autoradiographic studies and a beta-scintillator. Neuroimage 2007; 35(3):1086–1092.PubMedCrossRefGoogle Scholar
  50. Zane, P.A., Brindle, S.D., Gause, D.O., O’Buck, A.J., Raghavan, P.R., and Tripp, S.L. Physicochemical factors associated with binding and retention of compounds in ocular melanin of rats: Correlations using data from whole-body autoradiography and molecular modeling for multiple linear regression analysis. Pharm. Res. 1990; 7(9):935–941.PubMedCrossRefGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2011

Authors and Affiliations

  1. 1.Drug Metabolism and Pharmacokinetics, Translational SciencesNovartisBaselSwitzerland

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