Molecular interaction between lacidipine and biological membranes.
OBJECTIVE
To examine the molecular basis for the unique pharmacokinetics of lacidipine by defining interactions between lacidipine and biological membranes, which may explain the long clinical half-life of this calcium channel antagonist.


METHODS
Radiotracer analysis was used to determine the membrane partition coefficient and washout kinetics of lacidipine with membranes of different composition. Small-angle X-ray diffraction with angstrom resolution was used to determine the location of lacidipine in membranes.


RESULTS
Lacidipine had a high membrane partition coefficient, which decreased as cholesterol in the membrane increased, and a slow rate of membrane washout. The drug was found deep within the membrane's hydrocarbon core, which was consistent with the other membrane drug parameters.


CONCLUSIONS
Lacidipine's location and interaction within membranes may provide a longer duration of therapeutic action and can explain the unique pharmacokinetics of this drug.
Herbette
L G
LG
Department of Radiology, University of Connecticut Health Center, Farmington 06030.
Gaviraghi
G
G
Tulenko
T
T
Mason
R P
RP
D000818:Animals; D002121:Calcium Channel Blockers / Q000493:pharmacokinetics* / Q000627:therapeutic use; D015220:Calcium Channels / Q000378:metabolism*; D002417:Cattle; D002455:Cell Division / Q000187:drug effects; D002462:Cell Membrane / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism; D004095:Dihydropyridines / Q000493:pharmacokinetics* / Q000627:therapeutic use; D006207:Half-Life; D006801:Humans; D006973:Hypertension / Q000188:drug therapy; D066298:In Vitro Techniques; D008051:Lipid Bilayers; D008563:Membrane Lipids / Q000378:metabolism; D011869:Radioligand Assay; D014961:X-Ray Diffraction
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D004095:Dihydropyridines; D008051:Lipid Bilayers; D008563:Membrane Lipids; C060285:lacidipine; D002784:Cholesterol