Archives of Pharmacal Research

The Pharmaceutical Society of Korea (대한약학회)
권호 표지

Pharmacokinetics of PEG-Hemoglobin SB1, a Hemoglobin-Based Oxygen Carrier, after Its Intravenous Administration in Beagle Dogs

  • Kwon, Oh-Seung (Bioanalysis and Biotransformation Research Center, Korea Institute of Science and Technology) ;
  • Chung, Uoo-Tae (National Research Laboratory (NRL) of PK/PD, College of Pharmacy, Chungbuk National University) ;
  • Chung, Youn-Bok (National Research Laboratory (NRL) of PK/PD, College of Pharmacy, Chungbuk National University)
  • Published : 2004.02.01
Download PDF
⟨ Previous Next ⟩

Abstract

The purpose of the present study was to investigate the pharmacokinetics of PEG-hemoglobin SB 1, a modified bovine hemoglobin with polyethylene glycol, after its single and multiple administration in beagle dogs. For this purpose, the analytical method of free hemoglobin in the plasma was developed and validated. Excellent linearity ($r^2$=0.999) was observed in the calibration curve data, with the limit of quantification of 0.005 g/dL. The precision and the deviation of the theoretical values for accuracy were always within $\pm$15％ in both the between-and the within-day results. The method was tested by measuring the plasma concentrations following intravenous administration to beagle dogs and was shown to be suitable for pharmacokinetic studies. In a single dose study, the plasma half-life (t$_{1}$2/) increased and the total body clearance (Cl$_{t}$) decreased with the dose (i.e., 0.017 to 0.75 gHb/kg as PEG-hemoglobin SB1) in both sexes. The volume of distribution at steady-state (Vd$_{ss}$ ) showed no difference with the dose. In contrast, the values of t$_{1}$2/, CL$_{t}$ and the area under the plasma concentration-time curve (AUC) after the multiple dose were significantly different from those of the single dose administration. The values of t$_{1}$2/ in the multiple administration were about two times higher-than that of the single dose. As a result, t$_{1}$2/ of hemoglobin after the administration of PEG-hemoglobin SB1 was about 15-30 h, indicating the PEG modification of the hemoglobin lead to a prolongation of plasma concentration of the protein. Therefore, these observations suggested that the PEG modification of hemoglobin is potentially applicable in the hemoglobin-based therapeutics.tics.

Keywords

References

  1. Brunori, M., Noble, R. W, Antonini, E., and Wyman, J., The reaction of the isolated alpha and beta chains of human hemoglobin with oxygen and carbon monoxide. J. Biol. Chem., 225, 5238-5243 (1966)
  2. Chatterjee, R., Welty, E. V., Walder, R. Y., Pruitt, S. L., Rogers, P. H., Arnone, A. and Walder, J. A., Isolation and charac-terization of a new hemoglobin deritive cross-linked between the alpha chains (lysine 99 alpha l-lys 99 alpha 2). J. Biol. Chem., 261,9929-9937 (1986)
  3. Fago, A., Bendixen, E., Malte, H., and Webcr, R. E., The anodic hemoglobin of anguilla molecular basis for allosteric effects in a root-effect hemoglobin. J. Biol. Chem., 272, 15628-15635 (1997) https://doi.org/10.1074/jbc.272.25.15628
  4. Gould, S. A., Moore, E. E., Hoyt, D. B., Burch, J. M., Hae-nd, J. B., Garcia, J., DeWoskin, R., and Moss, G. S., The first randomized trial of human polymerized hemoglobin as blood substitute in acute trauma and emergent surgery. J. Am. Coll. Surg., 18, 113-122 (1998)
  5. Hardison, R. C., Chui, D. H. K., Riemer, C. R, Miller, W., Carver, M. F. H., Molchanova, T. P., Efremov, G. D., and Huisman, T H. J., Access to a syllabus to human hemoglobin variants (1996) via world wide web. Hemoglobin, 22, 113-127 (1998) https://doi.org/10.3109/03630269809092136
  6. Hess, J. R., Alternative oxygen carriers. Curr. Opin. Hematol., 3, 492-497 (1996a) https://doi.org/10.1097/00062752-199603060-00016
  7. Hess, J. R, Blood substitutes. Sem. Hematol., 33, 369-378 (1996b)
  8. Iwashita, Y., Yabuki, A., Yamaji, K., Iwasaki, K., Okami, T., Hirata, C., and Kosaka, K., A new resuscitation fluid 'stabilized hemoglobin' preparation a characteristics. Biomat. Artif. Cells Artif. Organs, 16, 271-280 (1988)
  9. Kasper, S., Walter, M., Grune, F., Bischoff, A., Erasmi, H., and Buzello, W., Effects of a hemoglobin-based oxygen carrier (HBOC-201) on hemodynamics and oxygen transport in patients undergoing preoperative hemodilution for elective abdominal aortic surgery. Anesth. Analg., 83, 921-927 (1996)
  10. Kluger, R., Wodzinska, J., Jones, R. T., Head, C., Fujita, T. S., and Shih, D. T., Three-point cross-linking: potential red cell substitutes from the reaction of trimesoyl tris-(methyl phosphate) with hemoglobin. Biochemistry, 31, 7551-7559(1992) https://doi.org/10.1021/bi00148a016
  11. Phillips, W. T., Klipper, R. W., Awasthi, V. D., Rudolph, A. S., Cliff, R., Kwasiborski, V., and Goins, B. A., Polyethylene glycol-modified liposome-encapsulated hemoglobin: a long circulating red cell substitute. J. Pharmacal. Exp. Ther., 288, 665-670 (1999)
  12. Przybelski, R. J., Daily, E. K., Kisicki, J. C., Mattia Gold-berg, C., Bounds, M. J., and Colburn, W. A., Phase I study of the safety and pharmacologic effects of diaspirin cross-linked hemoglobin solution. Crit. Care Med., 24,1993-2000 (1996) https://doi.org/10.1097/00003246-199612000-00011
  13. Reah, G., Bodenham, A. R., Maliick, A., Daily, E. K., and Przybelski, R J., Initial evaluation of diaspirin cross-linked hemoglobin (DCLHb) vasopressor in critically ill patients. Crit. Care Med., 25, 1480-1488 (1997) https://doi.org/10.1097/00003246-199709000-00014
  14. Ritchie, A. J., Hartshorn, S., Crosbie, A. E., Callingham, B. A., Latimer, R. D., and Vuylsteke, A., The action of diaspirin cross-linked haemoglobin blood substitute on human arterial bypass conduits. Eur. J. Cardiothorac. Surg., 18, 241-245 (2000) https://doi.org/10.1016/S1010-7940(00)00423-1
  15. Sakai, H., Tomiyama, K. I., Sou, K., Takeoka, S., and Tsuchida, E., Poly(ethylene glycol)-conjugation and deoxygenation enable long-term preservation of hemoglobin-vesicles as oxygen carriers in a liquid state. Bioconjug. Chem.,11, 425-432 (2000) https://doi.org/10.1021/bc990173h
  16. Savitsky, J. P., Doczi, J., Black, J., and Arnold, J. D., A clinical safety trial of stroma-free hemoglobin. Chin. Pharmacol. Ther., 23, 73-80 (1978)
  17. Scott, M. G., Kucik, D. F., Goodnough, L. T., and Monk, T. G., Blood substitutes: evolution and future applications. Clin. Chem., 43,1724-1731 (1997)
  18. Sharma, V. S., Traylor, T. G., and Gardiner, R, Reaction of nitric oxide with heme proteins and model compound of hemoglobin. Biochemistry, 26, 3837-3843 (1987) https://doi.org/10.1021/bi00387a015
  19. Suzuki, T., Takagi, T, and Ohta, S., Primary structure of a dimeric haemoglobin from the deep-sea seep clam calyptogena soyoae. Biochem. J., 260,177-182 (1989)
  20. Szebeni, J, Wassef, N. M., Hartman, K. R., Rudolph, A. S., and Alving, C. R., Complement activation in vitro by the red cell substitute, liposome-encapsulated hemoglobin: mechanism of activation and inhibition by soluble complement receptor type 1. Transfusion, 37,150-159 (1997) https://doi.org/10.1046/j.1537-2995.1997.37297203517.x
  21. Winslow, R., Hemoglobin-based red cell substitutes: unsolved issues and urther directions. In: Tuchida E, editor. Artificial Red Cell. Chichester: John & Sons, 17-30 (1995)