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K J Cook

Publications and source records attributed to K J Cook.

12 recordsLinked to original sources
PubMed1990

Development of a sensitive activity assay for high-volume evaluation of human renin inhibitory peptides in rat serum: results with U-71,038.

A sensitive activity assay for high volume evaluation of human renin inhibitory peptides (RIPs) in rat sera (range 2-80 ng/ml) was developed based on the low affinity of RIPs to rat renin and their high affinity to human renin. The utility of this activity assay was tested by measuring concentrations of a human RIP, U-71,038 (BOC-Pro-Phe-N-MeHis-Leu psi [CHOHCH2]Val-Ile-Amp), in rat sera, determined by the activity assay, by a sensitive radioimmunoassay (RIA), and by tracking tritiated drug. Rats were given radiolabeled drug as an intravenous bolus, and blood samples were collected at various times after dosing. The serum level of U-71,038 equivalents was determined by the three techniques. Whole blood was also counted for total radioactivity to evaluate the potential for U-71,038 incorporation into red blood cells. Results from the three serum assays indicate good agreement between the calculated U-71,038 equivalents for the 30 min and 1 hr collection times. The 2 and 4 hr collection times show excellent agreement for the activity assay and RIA; [3H]-U-71,038 determinations gave substantially higher values. Serum levels for U-71,038 determined 30 min after dosing averaged less than 300 ng equivalents/ml suggesting that less than 1% of the administered dose was in the systemic circulation at that time. Thus, U-71,038 was rapidly cleared. At the 4 hr collection time, the level of U-71,038 equivalents, as determined by activity assay and RIA, was ten times the in vitro IC50 for the renin inhibitory activity of U-71,038.(ABSTRACT TRUNCATED AT 250 WORDS)

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PubMedDate not supplied

Disposition, metabolism, and excretion of U-71038, a novel renin inhibitor peptide, in the rat.

The in vivo fate of U-71038 (Boc-Pro-Phe-N-MeHis-Leu psi [CHOHCH2] Val-Ile-(aminomethyl)pyridine), a potent renin inhibitor, was investigated in rats by single iv administration of tritium-labeled drug at a dose level of 5 mg/kg. The plasma concentrations of drug-related radioactivity diminished very rapidly during the first hour after dosing, with the initial concentrations measured at 2 min falling by more than 95% during the first 30 min. Estimates of the approximate half-life of this earliest phase of the plasma concentration-time curve gave an average value of 4 min. The residual amount of radioactivity after 30 min was cleared from the plasma more slowly, with trace levels still detected 48 hr after dosing. The radioactivity was recovered chiefly (91% of the dose) in feces, indicating biliary clearance as the primary route of elimination from systemic circulation. Urinary recoveries averaged 4% of the dose. Radio-HPLC profiling of plasma, urine, and bile extracts detected only a single radioactive drug-related component in these samples. Preparative HPLC was used to isolate this component from bile; mass spectral comparison to U-71038 confirmed its identity as the unchanged drug. Therefore, U-71038 does not undergo significant systemic metabolism in this species and is eliminated in bile and urine in intact form. Distribution of drug-related radioactivity was very rapid to most of the organs and tissues that were sampled, with the exception of very limited penetration into the central nervous system. Highest tissue levels of tritium were generally found in organs associated with elimination (liver, intestine, kidney) and in thyroid.

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