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

Patel, K., Rademaker, M. T., Kirkpatrick, C. M. J., Charles, C. J., Fisher, S., Yandle, T. G. and Richards, A. M. (2012) Comparative pharmacokinetics and pharmacodynamics of urocortins 1, 2 and 3 in healthy sheep. British Journal of Pharmacology, 166 6: 1916-1925. doi:10.1111/j.1476-5381.2012.01904.x

Author Patel, K.
Rademaker, M. T.
Kirkpatrick, C. M. J.
Charles, C. J.
Fisher, S.
Yandle, T. G.
Richards, A. M.
Total Author Count Override 7
Title Comparative pharmacokinetics and pharmacodynamics of urocortins 1, 2 and 3 in healthy sheep
Journal name British Journal of Pharmacology   Check publisher's open access policy
ISSN 0007-1188
Publication date 2012-07
Sub-type Article (original research)
DOI 10.1111/j.1476-5381.2012.01904.x
Volume 166
Issue 6
Start page 1916
End page 1925
Total pages 10
Place of publication Chichester, West Sussex, United Kingdom
Publisher John Wiley & Sons
Collection year 2013
Language eng
Formatted 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 and less prolonged for Ucn2 and Ucn3 than Ucn1. Similar and physiologically plausible estimated baseline (E 0) effects were exhibited by all Ucns, whereas EC 50 values were generally greater for Ucn1.

CONCLUSIONS AND IMPLICATIONS: Relative to Ucn1, both the PK and haemodynamic responses to Ucn2 and Ucn3 occurred more rapidly. Our data provide important comparative information, useful to the rational design of future clinical studies.
Keyword Pharmacokinetics
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2013 Collection
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