Enantioselective pharmacokinetics of the enantiomers of clevidipine following intravenous infusion of the racemate in essential hypertensive patients.
The aim of the study was to characterize the individual pharmacokinetics of (-)-R- and (+)-S-clevidipine following intravenous constant rate infusion of rac-clevidipine to essential hypertensive patients. Twenty patients received three out of five randomized treatments with clevidipine. The pharmacokinetics of the separate enantiomers were evaluated by compartmental analysis of blood concentrations vs. time curves using the population approach. The derived pharmacokinetic parameters were used to simulate the time for 50 and 90% postinfusion decline following various infusion times of rac-clevidipine. A two-compartment model was used to describe the dispositions of the enantiomers; there were only minor differences between the estimated pharmacokinetic parameters of the separate enantiomers. The mean blood clearance values of (-)-R- and (+)-S-clevidipine were 0.103 and 0.096 l/min/kg, and the corresponding volumes of distribution at steady state were 0.39 and 0.54 l/kg, respectively. The context-sensitive half-time was approximately 2 min regardless of stereochemical configuration, and a 90% decline in concentration was achieved approximately 8 min postinfusion for (-)-R-clevidipine and 11 min for (+)-S-clevidipine, following clinically relevant infusion times with clevidipine. In conclusion, both enantiomers are high-clearance compounds with similar blood clearance values. The volume of distribution for the enantiomers is slightly different, presumably due to differences in the protein binding. From a pharmacokinetic point of view, the use of a single enantiomer as an alternative to the racemic clevidipine will not offer any clinical advantages.
AstraZeneca, R&D Mölndal, Mölndal, Sweden. Hans.Ericsson@astrazeneca.com
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Ericsson
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Schwieler
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Lindmark
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Löfdahl
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Thulin
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Regårdh
D000959:Antihypertensive Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001825:Body Fluid Compartments; D002121:Calcium Channel Blockers / Q000097:blood / Q000493:pharmacokinetics; D003198:Computer Simulation; D018592:Cross-Over Studies; D006801:Humans; D006973:Hypertension / Q000097:blood / Q000188:drug therapy / Q000378:metabolism*; D007262:Infusions, Intravenous; D008875:Middle Aged; D008954:Models, Biological; D010919:Placebos; D011725:Pyridines / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D016037:Single-Blind Method; D013237:Stereoisomerism
D000959:Antihypertensive Agents; D002121:Calcium Channel Blockers; D010919:Placebos; D011725:Pyridines; C118563:clevidipine