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Precipitation of the renin inhibitor ditekiren upon i.v. infusion; in vitro studies and their relationship to in vivo precipitation in the cynomolgus monkey. 1991

S R Davio, and M M McShane, and T J Kakuk, and R M Zaya, and S L Cole
Upjohn Company, Kalamazoo, Michigan 49001.

Ditekiren is a pseudo-octapeptide being developed as an inhibitor of human renin. Preclinical drug safety studies with this drug involved continuous i.v. infusions through indwelling catheters in the right internal jugular vein of the cynomolgus monkey for up to 30 days. The following physiocochemical properties of ditekiren make it susceptible to intravascular precipitation immediately following iv infusion: (1) the water solubility of ditekiren is high at acidic pH where the drug is formulated (pH 4) but low at physiologic pH, and (2) the water solubility of ditekiren decreases by roughly 50% from room temperature (25 degrees C) to physiologic temperature (37 degrees C). Studies of 28- and 30-day infusion durations revealed intravascular precipitation in monkeys using drug solutions and rates of infusion that were expected to be precipitation-free, based on the solubility of ditekiren and assumptions about blood flow in the monkey right internal jugular vein. Therefore, an in vitro apparatus was used to study the relationship among the drug concentration in the infusate, the rate of infusion, and the occurrence of precipitation in a fluid stream of phosphate-buffered bovine serum albumin solution (a facsimile of plasma). Maximum rates of infusion without precipitation were determined for a range of concentrations of drug in two separate formulations. Infusion conditions identified by the in vitro method as precipitation-free were then tried in a definitive 14-day monkey study. Of 24 monkeys infused with solutions of ditekiren, none showed evidence of intravascular precipitation.(ABSTRACT TRUNCATED AT 250 WORDS)

UI MeSH Term Description Entries
D007262 Infusions, Intravenous The long-term (minutes to hours) administration of a fluid into the vein through venipuncture, either by letting the fluid flow by gravity or by pumping it. Drip Infusions,Intravenous Drip,Intravenous Infusions,Drip Infusion,Drip, Intravenous,Infusion, Drip,Infusion, Intravenous,Infusions, Drip,Intravenous Infusion
D007601 Jugular Veins Veins in the neck which drain the brain, face, and neck into the brachiocephalic or subclavian veins. Jugular Vein,Vein, Jugular,Veins, Jugular
D008252 Macaca fascicularis A species of the genus MACACA which typically lives near the coast in tidal creeks and mangrove swamps primarily on the islands of the Malay peninsula. Burmese Long-Tailed Macaque,Crab-Eating Monkey,Cynomolgus Monkey,M. f. aurea,M. fascicularis,Macaca fascicularis aurea,Monkey, Crab-Eating,Monkey, Cynomolgus,Crab-Eating Macaque,Burmese Long Tailed Macaque,Crab Eating Macaque,Crab Eating Monkey,Crab-Eating Macaques,Crab-Eating Monkeys,Cynomolgus Monkeys,Long-Tailed Macaque, Burmese,Macaque, Burmese Long-Tailed,Macaque, Crab-Eating,Monkey, Crab Eating
D009842 Oligopeptides Peptides composed of between two and twelve amino acids. Oligopeptide
D012083 Renin A highly specific (Leu-Leu) endopeptidase that generates ANGIOTENSIN I from its precursor ANGIOTENSINOGEN, leading to a cascade of reactions which elevate BLOOD PRESSURE and increase sodium retention by the kidney in the RENIN-ANGIOTENSIN SYSTEM. The enzyme was formerly listed as EC 3.4.99.19. Angiotensin-Forming Enzyme,Angiotensinogenase,Big Renin,Cryorenin,Inactive Renin,Pre-Prorenin,Preprorenin,Prorenin,Angiotensin Forming Enzyme,Pre Prorenin,Renin, Big,Renin, Inactive
D006863 Hydrogen-Ion Concentration The normality of a solution with respect to HYDROGEN ions; H+. It is related to acidity measurements in most cases by pH pH,Concentration, Hydrogen-Ion,Concentrations, Hydrogen-Ion,Hydrogen Ion Concentration,Hydrogen-Ion Concentrations
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D012542 Scattering, Radiation The diversion of RADIATION (thermal, electromagnetic, or nuclear) from its original path as a result of interactions or collisions with atoms, molecules, or larger particles in the atmosphere or other media. (McGraw-Hill Dictionary of Scientific and Technical Terms, 6th ed) Radiation Scattering,Radiation Scatterings,Scatterings, Radiation

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