Pharmacokinetics and pharmacodynamics of CI-992 following intravenous and oral administration to cynomolgus monkeys.

The purpose of this study was to characterize CI-992 pharmacokinetics and pharmacokinetics/pharmacodynamics (PK/PD) in sodium deplete monkeys. Panels of monkeys were administered CI-992 as a 1 h intravenous infusions (0.1 and 1 mg kg-1) or as single oral doses (0, 10, 50, and 100 mg kg-1). Mean arterial blood pressure (MABP) was monitored and serial blood samples were collected up to 24 h postdose. Plasma CI-992 concentrations were quantitated by radioimmunoassay. Pharmacokinetic parameters were calculated by noncompartmental methods. PK/PD relationships were assessed by standard methods. Oral bioavailability of CI-992 in the monkeys was < 2%; steady-state volume of distribution was 0.67 L kg-1; clearance was 10.4 mL min-1 kg-1. Following oral administration, tmax generally occurred 6-9 h postadministration; plasma CI-992 concentrations increased with increasing dose between 10 and 50 mg kg-1, but did not change appreciably from 50 to 100 mg kg-1. After intravenous administration, change in MABP was correlated with plasma CI-992 concentration through an effect compartment model in which the maximum achievable effect was a 22 mm Hg decrease in MABP; the steady-state concentration which produced half the maximum effect was 11 ng mL-1. Following the 10 mg kg-1 oral dose the maximum decrease in MABP was 19.1 mm Hg; higher doses did not produce greater maximum response but increased the duration of action. In contrast to observations following intravenous administration, a trend for decreasing MABP with increasing plasma CI-992 was not apparent following oral CI-992 administration.

Renin inhibitors containing isosteric replacements of the amide bond connecting the P3 and P2 sites.

Renin inhibitors having 13 different isosteres connecting the P3 and P2 positions have been prepared. Synthetic routes and in vitro activity exhibited by these compounds are discussed. The two most potent compounds, 47 and 48, contained the hydroxyethylene isostere, psi [CHOHCH2], and had IC50 values of 61 and 22 nM, respectively.

The clinical pharmacokinetics of quinapril.

Quinapril (Q) and quinaprilat (QT) pharmacokinetics are dose proportional following single oral 2.5- to 80-mg Q doses. Q absorption and hydrolysis to QT is rapid with peak Q and QT concentrations occurring one and two hours postdose, respectively. Peak plasma QT concentrations were approximately fourfold higher than those of Q (923 vs 207 ng/mL following 40-mg Q). Dose-proportional QT area under the curve and dose-independent percent of dose excreted in urine as QT demonstrate that the extent of Q conversion to QT is constant over the dose range studied. Q and QT were eliminated from plasma with apparent half-lives of 0.8 and 1.9 hours and apparent plasma clearances of 1,850 and 220 mL/min, respectively, over the 2.5- to 80-mg dose range. Following oral 14C-Q, 61% and 37% of radiolabel was recovered in urine and feces, respectively. Q plus QT accounted for 46% of radioactivity circulating in plasma and 56% of that excreted in urine. Metabolism to compounds other than QT is not extensive. Two diketopiperazine metabolites of Q have been identified in plasma and urine, with approximately 6% of an administered dose excreted in urine as each of these metabolites. Peak plasma concentrations of these metabolites are similar to that of Q, and each is eliminated rapidly with a half-life of approximately one hour. Urinary excretion profiles indicate the presence of other minor metabolites. In summary, the absorption of Q and conversion to QT is rapid and dose-proportional, subsequent clearance of both Q and QT is independent of dose, and metabolism to compounds other than QT is not extensive.

Metabolic disposition of isoxicam in man, monkey, dog, and rat.

Isoxicam a new nonsteroidal antiinflammatory agent was radiolabeled with 14C at the 3-position of the benzothiazine nucleus. It was well absorbed following peroral administration to man, monkey, dog, and rat, reaching peak plasma concentrations in 4-8 hr. Over 90% of the plasma radioactivity was due to unchanged drug. Plasma elimination half-lives were 22-45 hr in man and 49-53 hr in dogs and 20-35 hr in rats and monkeys. Isoxicam was distributed to most tissues in rats, but the tissue-plasma ratio did not exceed unity, indicating a small volume of distribution. It was extensively metabolized with only a few per cent of the dose appearing as unchanged drug in the urine. The principal urinary metabolite in man was formed by hydroxylation of the methyl group on the isoxozole ring and accounted for 30-35% of an isoxicam dose. In the rat, oxoacetic acid, the major urinary metabolite, was formed by opening of the benzothiazine ring followed by hydrolytic cleavage of the C-3 to N-2 bond. In addition to the hydroxymethyl and oxoacetic acid, two unknown metabolites, accounting for only a small percentage of dose, were detected in the urine of all four species. Urinary excretion of 14C activity accounted for about 60% of a dose in man and rats, 31% in monkeys, and 17% in dogs. These results indicate that there is only a quantitative rather than a qualitative species difference in the metabolic disposition of isoxicam.

Biological and chemical properties of the epidioxide isomer of abscisic Acid and its rearrangement products.

The growth inhibitory activity of the epidioxide (II), a precursor in the synthesis of abscisic acid (ABA), has been confirmed with additional assay systems. Under physiological conditions the epidioxide is rearranged to give ABA and an isomer of ABA which has probably the structure V. This major product has very low, if any, biological activity. The biological activity of the epidioxide is explained by its partial conversion (about 20%) to ABA. The reaction rate was enhanced by heavy metal ions and decreased by EDTA. At pH 12.5, the decomposition of the epidioxide is slower than it is near neutrality and ABA is the predominant product. In the biological systems studied the activity of the epidioxide can be accounted for by nonenzymatic conversion to ABA.