Clevidipine is a new ultrashort-acting
dihydropyridine calcium antagonist developed for blood pressure regulation during cardiac surgery. When given locally to the ischemic and reperfused myocardium,
clevidipine exerts a cardioprotective effect that varies depending on the timing of administration during
ischemia. The current study explored the pharmacokinetics of
clevidipine when administered locally into the coronary circulation.
Pentobarbital-anesthetized pigs were randomly divided into four groups, of which three were subjected to
myocardial ischemia through
ligation of the left anterior descending coronary artery (LAD) for 15, 35, or 45 minutes (n = 4 in each group). The fourth group (n = 4) was not subjected to LAD occlusion and acted as nonischemic controls.
Clevidipine (0.3 nmol/kg per minute) was infused over a period of 5 minutes through a
catheter distal to the LAD
ligation in the ischemic pigs, or at the corresponding site of the nonligated LAD in the nonischemic pigs. Following release of the LAD
ligation, or in the nonligated group following the
drug infusion, the pigs were subjected to 60 minutes of reperfusion. Simultaneous blood samples were obtained for analysis of
clevidipine from the femoral artery and the coronary vein during reperfusion and during
drug infusion in the nonischemic pigs. Blood samples for estimating the in vitro hydrolysis rate both in whole blood and in plasma were also obtained. In nonischemic hearts,
clevidipine reached a steady state level in the coronary venous blood of about 30 nM during the infusion. The concentration declined almost to the detection limit (1 nM) within 3 minutes of the end of infusion. The mean blood clearance of
clevidipine was calculated to be 0.17 l/min per kilogram, and the estimated half-life was 0.5 minute. In animals subjected to different periods of
ischemia, very low levels of
clevidipine were detected in the coronary venous blood only during the first 2 minutes of reperfusion. There were no detectable levels in the arterial blood at any time. Blood concentration profiles of
clevidipine did not differ with the length of
myocardial ischemia. The in vitro half-life in pig blood was 13 minutes, and the corresponding half-life in plasma was 111 minutes. At a dose known to exert cardioprotection when given as an intracoronary injection, the systemic concentration of
clevidipine does not reach pharmacologically active levels.
Clevidipine has an ultrashort blood half-life, and ischemic duration of up to 45 minutes does not seem to change the cardiac metabolism of this
drug. Thus, it represents a pharmacological tool well suited for the study of time windows in cardioprotection. Moreover, considering the possibility of exerting myocardioprotection without any systemic effects, it could be an interesting compound to test in a clinical setting.