Stereoselective pharmacokinetics of cisapride in healthy volunteers and the effect of repeated administration of grapefruit juice
Authors: Desta Zeruesenay , Kivistö Kari T. , Lilja Jari J. , Backman Janne T. , Soukhova Nadia , Neuvonen Pertti J. , Flockhart David A. 
Published: March 2003

Aims  To determine whether the pharmacokinetics of cisapride and its interaction with grapefruit juice are stereoselective.

Methods  The study was a randomized, two‐phase cross 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.

Results  This study showed that cisapride pharmacokinetics are stereoselective. In control (water treated) subjects, the mean Cmax (30 ± 13.6 ng ml−1; P = 0.0008) and AUC(0, ∞) (201 ± 161 ng ml−1 h; P = 0.029) of (−)‐cisapride were significantly higher than the Cmax (10.5 ± 3.4 ng ml−1) and AUC(0, ∞) (70 ± 51.5 ng ml−1 h) of (+)‐cisapride. There 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 treated group, grapefruit juice significantly increased the mean Cmax of (−)‐cisapride from 30 ± 13.6–55.5 ± 18 ng ml−1 (95% CI on mean difference, −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, ∞) of (−)‐cisapride was increased from 201 ± 161 to 521.6 ± 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 tmax was also significantly increased for both enantiomers (from 1.35 to 2.8 h for (−)‐cisapride and from 1.75 to 2.9 h for (+)‐cisapride in the control and grapefruit juice group, respectively; P < 0.05). The t½ 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‐stereoselective interaction. We found no significant difference in mean QTc intervals between the water and grapefruit juice treated groups.

Conclusions  The pharmacokinetics of cisapride is stereoselective. 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 exhibit stereoselective pharmacodynamic actions. If they do, determination of plasma concentrations of the individual enantiomers as opposed to those of racemic cisapride may better predict the degree of drug interaction, cardiac safety and prokinetic efficacy of cisapride.