Abstract
Ditekiren (U-71038; Boc-Pro-Phe-N-MeHis-Leu-Ψ[CHOHCH2]-Val-Ile-aminomethyl)pyridine) is a potent renin inhibitor peptide and was formulated for clinical intravenous administration in acidified dextrose. This formulation of ditekiren was evaluated in vitro with human and monkey plasma as to its potential for forming a precipitate either of drug or of plasma proteins. Analysis by centrifugation showed that no drug precipitation occurred in plasma from either species at concentrations 25 times higher than anticipated in clinical studies. Results obtained by turbidimetry indicated that formulated ditekiren did not cause aggregation of human platelets or flocculation of proteins at concentrations approaching the solubility limit of the drug in plasma. Ditekiren or vehicle also caused no detectable lysis of red cells at concentrations representing 10 times the maximum clinical level. Therefore, ditekiren solutions as formulated are judged completely compatible with blood and plasma upon clinical intravenous administration.
Similar content being viewed by others
REFERENCES
D. T. Pals, S. Thaisrivongs, J. A. Lawson, W. M. Kati, S. R. Turner, G. L. DeGraff, D. W. Harris, and G. A. Johnson. An orally active inhibitor of renin. Hypertension (Dallas) 8:1105–1112 (1986).
W. J. Greenlee. Renin inhibitors. Med. Res. Rev. 10:173–236 (1990).
J. C. Greenfield, K. J. Cook, and I. A. O'Leary. Disposition, metabolism, and excretion of U-71038, a novel renin inhibitor peptide, in the rat. Drug Metab. Dispos. 17:518–525 (1989).
J. Luderer, M. Froeschke, L. Wathen, W. Harrelson, W. Bryan, J. Bokros, S. Mohrland, and C. Metzler. Preliminary human experience with the renin inhibitor ditekiren. Clin. Pharmacol. Ther. 47:200 (1990).
J. J. Ferry, D. B. Lakings, S. K. Closson, and J. R. Luderer. Comparative pharmacokinetics of the new renin inhibitor ditekiren in sodium replete and sodium deplete healthy volunteers. Clin. Pharmacol. Ther. 47:157 (1990).
S. Thaisrivongs, D. T. Pals, D. W. Harris, W. M. Kati, and S. R. Turner. Design and synthesis of a potent and specific renin inhibitor with a prolonged duration of action in vivo. J. Med. Chem. 29:2088–2093 (1986).
A. Osol (ed.), Remington's Pharmaceutical Sciences, 16th ed., Mack, Easton, Pennsylvania, 1980, p. 769.
A. Osol (ed.), Remington's Pharmaceutical Sciences, 16th ed., Mack, Easton, Pennsylvania, 1980, p. 1506.
W. J. Husa and J. R. Adams. Isotonic solutions. II. The permeability of red corpuscles to various substances. J. Am. Pharm. Assoc. 33:329–332 (1944).
T. S. Grosicki and W. J. Husa. Isotonic solutions. III. Amino acids and sugars. J. Am. Pharm. Assoc. Sci. Ed. 43:632–635 (1954).
S. R. Davio, M. M. McShane, T. J. Kakuk, R. M. Zaya, and S. L. Cole. Precipitation of the renin inhibitor ditekiren upon i.v. infusion; In vitro studies and their relationship to in vivo precipitation in the cynomolgus monkey. Pharm. Res. 8:80–83 (1991).
R. Zelis, J. Longhurst, R. J. Capone, and D. T. Mason. A comparison of regional blood flow and oxygen utilization during dynamic forearm exercise in normal subjects and patients with congestive heart failure. Circulation 50:137–143 (1974).
S. J. Loux and J. C. Greenfield. Unpublished observations.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Greenfield, J.C., Loux, S.J., Sood, V.K. et al. In Vitro Evaluation of the Plasma and Blood Compatibility of a Parenteral Formulation for Ditekiren, a Novel Renin Inhibitor Pseudopeptide. Pharm Res 8, 475–479 (1991). https://doi.org/10.1023/A:1015847027254
Issue Date:
DOI: https://doi.org/10.1023/A:1015847027254