Stereoselective pharmacokinetics of cisapride in healthy volunteers and the effect of repeated administration of grapefruit juice

Aims To determine whether the pharmacokinetics of cisapride and its interac tion with grapefruit Juice are stereoselective. Methods The study was a randomized, two-phase cross over design with a wash out period of 2 weeks. Ten healthy volunteers were pretreated with either w ater or 200 ml double strength grapefruit juice three times a day for 2 day s. On the 3rd each subject ingested a single 10 mg dose of rac-cisapride ta blet. Double strength grapefruit juice (200 ml) or water was administered d uring cisapride dosing and 0.5 and 1.5 h thereafter. Blood samples were col lected before and for 32 h after cisapride administration. Plasma concentra tions of cisapride enantiomers were measured by a chiral h.p.l.c. method. A standard 12-lead ECG was recorded before cisapride administration (baselin e) and 2, 5, 8, and 12 h later. Results This study showed that cisapride pharmacokinetics are stereoselecti ve. In control (water treated) subjects, the mean C-max (30 +/- 13.6 ng ml( -1); P = 0.0008) and AUC(0, infinity) (201 +/- 161 ng ml(-1) h; P = 0.029) of (-)-cisapride were significantly higher than the C-max (10.5 +/- 3.4 ng ml(-1)) and AUC(0, infinity) (70 +/- 51.5 ng ml(-1) h) of (+)-cisapride. Th ere was no marked difference in elimination half-life between (-)-cisapride (4.7 +/- 2.7 h) and (+)-cisapride (4.8 +/- 3 h). Compared with the water t reated group, grapefruit juice significantly increased the mean C-max of (- )-cisapride from 30 +/- 13.6-55.5 +/- 18 ng ml(-1) (95% CI on mean differen ce, -33, -17; P = 0.00005) and of (+)-cisapride from 10.5 +/- 3.4 to 18.4 /- 6.2 ng ml(-1) (95% CI on mean difference, -11.8, -3.9, P = 0.00015). The mean AUC(0, infinity) of (-)-cisapride was increased from 201 +/- 161 to 5 21.6 +/- 303 ng ml(-1) h (95% CI on mean difference, -439, -202; P = 0.0002 ) and that of (+)-cisapride from 70 +/- 51.5 to 170 +/- 91 ng ml(-1) h (95% CI on mean difference, -143, -53; P = 0.0005). The t(max) was also signifi cantly increased for both enantiomers. (from 1.35 to 2.8 h for (-)-cisaprid e and from 1.75 to 2.9 h for (+)-cisapride in the control and grapefruit ju ice group, respectively; P < 0.05). The t(1/2) of (-)-cisapride was signifi cantly increased by grapefruit juice, while this change did not reach signi ficant level for (+)-cisapride. The proportion of pharmacokinetic changes b rought about by grapefruit juice was similar for both enantiomers, suggesti ng non-stereoselective interaction. We found no significant difference in m ean QTc intervals between the water and grapefruit juice treated groups. Conclusions The pharmacokinetics of cisapride is stereoselective. Grapefrui t juice elevates plasma concentrations of both (-)- and (+)-cisapride, prob ably through inhibition of CYP3A in the intestine. At present, there are no data on whether the enantiomers exhibit stereoselective pharmacodynamic ac tions. If they do, determination of plasma concentrations of the individual enantiomers as opposed to those of racemic cisapride may better predict th e degree of drug interaction, cardiac safety and prokinetic efficacy of cis apride.