Pharmacokinetics and pharmacodynamics of clevidipine in healthy volunteers after intravenous infusion.
OBJECTIVE
To determine the pharmacokinetics and pharmacodynamics of clevidipine, a new ultrashort-acting calcium antagonist, in healthy male volunteers following a constant rate infusion.


METHODS
Eight healthy male volunteers received 1030 nmol x min(-1) of clevidipine together with a tracer dose of 3[H]-clevidipine for 1 h as an i.v. infusion. Frequent venous blood samples and effect recordings were obtained during ongoing infusion and up to 32 h following termination of the infusion. The excretion of radioactivity in urine and faeces was followed for 7 days.


RESULTS
A two-compartment model gave the best fit to the individual clevidipine blood levels, resulting in a mean blood clearance of 0.14 (0.03) l x min(-1) x kg(-1) and a mean volume of distribution at steady state of 0.6 (0.1) l x kg(-1). The initial half-life was 1.6 (0.3) min, and the terminal half-life was 15 (5) min. The maximum concentration of the metabolite H 152/81 was reached 2.2 (1.3) min following termination of the infusion. The mean terminal half-life of the inactive primary metabolite was 9.5 (0.8) h and the mean recovery of the radioactive dose reached 83 (3)%. Following termination of the 1 h infusion, the effect on blood pressure (BP) and heart rate was back to pre-dose values within 15 min.


CONCLUSIONS
Clevidipine is a high clearance drug, which is rapidly metabolized to the corresponding inactive acid. The tmax value of the primary metabolite, and a virtually identical value of the initial half-life and the half-life for elimination from the central compartment, indicate that the initial rapid decline of the post-infusion blood levels is mainly due to elimination rather than distribution. The duration of action of clevidipine is short.
Ericsson
H
H
Pharmacokinetics and Drug Metabolism, Mölndal, Sweden. Hans.Ericsson@ hassle.se.astra.com
Fakt
C
C
Höglund
L
L
Jolin-Mellgård
A
A
Nordlander
M
M
Sunzel
M
M
Regårdh
C G
CG
D000328:Adult; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects*; D006339:Heart Rate / Q000187:drug effects*; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D011725:Pyridines / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D013997:Time Factors
D000959:Antihypertensive Agents; D011725:Pyridines; C118563:clevidipine