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.
Cook
J A
JA
Department of Pharmacology, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, Ann Arbor, MI 48105, USA. cookj@aa.wl.com
Burger
P J
PJ
Michniewicz
B M
BM
Nordblom
G D
GD
Hicks
G W
GW
Kaplan
C
C
Ryan
M J
MJ
D000284:Administration, Oral; D000818:Animals; D000959:Antihypertensive Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D001682:Biological Availability; D001794:Blood Pressure / Q000187:drug effects; D004151:Dipeptides / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D007262:Infusions, Intravenous; D008252:Macaca fascicularis; D008297:Male; D011480:Protease Inhibitors / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D012964:Sodium / Q000172:deficiency; D000092502:Renin Inhibitors
D000959:Antihypertensive Agents; D004151:Dipeptides; D011480:Protease Inhibitors; D012964:Sodium; D000092502:Renin Inhibitors; C085688:CI 992