| Disease | TO DETERMINE WHETHER THE PHARMACOKINETICS OF CISAPRIDE AND ITS INTERACTION WITH GRAPEFRUIT JUICE ARE STEREOSELECTIVE. THE STUDY WAS A RANDOMIZED, TWO-PHASE OVER DESIGN WITH A WASHOUT PERIOD OF 2 WEEKS. TEN HEALTHY VOLUNTEERS WERE PRETREATED
WITH EITHER WATER OR 200 ML DOUBLE STRENGTH GRAPEFRUIT JUICE THREE TIMES A DAY FOR 2 DAYS. ON THE 3RD EACH SUBJECT INGESTED A SINGLE 10 MG DOSE OF RAC-CISAPRIDE TABLET. DOUBLE STRENGTH GRAPEFRUIT JUICE (200 ML) OR WATER WAS ADMINISTERED DURING
CISAPRIDE DOSING AND 0.5 AND 1.5 H THEREAFTER. BLOOD SAMPLES WERE COLLECTED BEFORE AND FOR 32 H AFTER CISAPRIDE ADMINISTRATION. PLASMA CONCENTRATIONS OF CISAPRIDE ENANTIOMERS WERE MEASURED BY A CHIRAL H.P.L.C. METHOD. A STANDARD 12-LEAD ECG
WAS RECORDED BEFORE CISAPRIDE ADMINISTRATION (BASELINE) AND 2, 5, 8, AND 12 H LATER. THIS STUDY SHOWED THAT CISAPRIDE PHARMACOKINETICS ARE STEREOSELECTIVE. THE T1/2 OF (-)-CISAPRIDE WAS SIGNIFICANTLY INCREASED BY GRAPEFRUIT JUICE, WHILE THIS
CHANGE DID NOT REACH SIGNIFICANT LEVEL FOR (+)-CISAPRIDE. THE PROPORTION OF PHARMACOKINETIC CHANGES BROUGHT ABOUT BY GRAPEFRUIT JUICE WAS SIMILAR FOR BOTH ENANTIOMERS, SUGGESTING NON-STEORSELECTIVE INTERACTION. WE FOUND NO SIGNIFICANT DIFFERENCE
IN MEAN QTC INTERVALS BETWEEN THE WATER AND GRAPEFRUIT JUICE TREATED GROUPS. GRAPEFRUIT JUICE ELEVATES PLASMA CONCENTRATIONS OF BOTH (-)- AND (+)-CISAPRIDE, PROBABLY THROUGH INHIBITION OF CYP3A IN THE INTESTINE. AT PRESENT, THERE ARE NO DATA
ON WHETHER THE ENANTIOMERS EXHIBITS STEREOSLECTIVE PHARMACODYNAMIC ACTIONS. IF THEY DO, DETERMINATION OF PLASMA CONCENTRATIONS OF THE INDIVIDUAL ENANTIOMERS AS OPPOSED TO THOSE OF RACEMIS CISAPIDE MAY BETTER PREDICT THE DEGREE OF DRUG
INTERACTION, CARDIAC SAFETY AND PROKINETIC EFFICACY OF CISAPRIDE. |