Comparative pharmacokinetics and pharmacodynamics of urocortins 1, 2 and 3 in healthy sheep.

British Journal of Pharmacology
K PatelA Mark Richards

Abstract

BACKGROUND AND PURPOSE The urocortin (Ucn) peptides are emerging as potential therapeutic targets for heart disease. However, pharmacokinetic (PK) and pharmacodynamic (PD) data are lacking. Therefore, we investigated the PK/PD for all three Ucns. EXPERIMENTAL APPROACH Seven sheep received 1 µg·kg(-1) boluses of Ucn1, Ucn2 and Ucn3. Population PK/PD models were developed to describe the time course of the haemodynamic effects. RESULTS The population estimate for Ucn1 clearance (0.486 L·h(-1)) was lower than that for Ucn2 (21.7 L·h(-1)) and Ucn3 (220 L·h(-1)), while steady-state volumes of distribution were similar for Ucn1 and Ucn2 (∼8 L) but substantially larger for Ucn3 (23.5 L). Ucn1 disposition was adequately described by a two-compartment model, with a one-compartment model required for Ucn2 and Ucn3. The half-life for Ucn1 was 2.9 h (α phase) and 8.3 h (β phase), and 15.7 and 4.4 min for Ucn2 and Ucn3 respectively. All Ucns produced significant increases in heart rate, cardiac output and left ventricular systolic and mean arterial pressures, and decreases in left atrial pressure and peripheral resistance. Delayed-effect pharmacodynamic models best described the time course of haemodynamic responses, with effects more rapid...Continue Reading

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