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

Zeruesenay Desta, Kari T. Kivistö, Jari J. Lilja, Janne T. Backman, Nadia Soukhova, Pertti J. Neuvonen, David A. Flockhart

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

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 (4.8plusmn;3 h). Compared with the water treated group, grapefruit juice significantly increased the mean Cmax of (-)-cisapride from 30plusmn;13.6-55.5plusmn;18 ng ml-1 (95% CI on mean difference, -33,-17; P=0.00005) and of (+)-cisapride from 10.5plusmn;3.4 to 18.4plusmn;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 201plusmn;161 to 521.6plusmn;303 ng ml-1 h (95% CI on mean difference, -439, -202; P=0.0002) and that of (+)-cisapride from 70plusmn;51.5 to 170plusmn;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; P1/2 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-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.

Original languageEnglish (US)
Pages (from-to)399-407
Number of pages9
JournalBritish Journal of Clinical Pharmacology
Volume52
Issue number4
DOIs
StatePublished - 2001
Externally publishedYes

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Cisapride
Citrus paradisi
Healthy Volunteers
Pharmacokinetics
Water
Area Under Curve

Keywords

  • Cisapride
  • Grapefruit juice
  • Pharmacokinetics
  • Stereoselectivity

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Pharmacology, Toxicology and Pharmaceutics(all)

Cite this

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

In: British Journal of Clinical Pharmacology, Vol. 52, No. 4, 2001, p. 399-407.

Research output: Contribution to journalArticle

Desta, Zeruesenay ; Kivistö, Kari T. ; Lilja, Jari J. ; Backman, Janne T. ; Soukhova, Nadia ; Neuvonen, Pertti J. ; Flockhart, David A. / Stereoselective pharmacokinetics of cisapride in healthy volunteers and the effect of repeated administration of grapefruit juice. In: British Journal of Clinical Pharmacology. 2001 ; Vol. 52, No. 4. pp. 399-407.
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abstract = "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 (4.8plusmn;3 h). Compared with the water treated group, grapefruit juice significantly increased the mean Cmax of (-)-cisapride from 30plusmn;13.6-55.5plusmn;18 ng ml-1 (95{\%} CI on mean difference, -33,-17; P=0.00005) and of (+)-cisapride from 10.5plusmn;3.4 to 18.4plusmn;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 201plusmn;161 to 521.6plusmn;303 ng ml-1 h (95{\%} CI on mean difference, -439, -202; P=0.0002) and that of (+)-cisapride from 70plusmn;51.5 to 170plusmn;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; P1/2 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-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.",
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author = "Zeruesenay Desta and Kivist{\"o}, {Kari T.} and Lilja, {Jari J.} and Backman, {Janne T.} and Nadia Soukhova and Neuvonen, {Pertti J.} and Flockhart, {David A.}",
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TY - JOUR

T1 - Stereoselective pharmacokinetics of cisapride in healthy volunteers and the effect of repeated administration of grapefruit juice

AU - Desta, Zeruesenay

AU - Kivistö, Kari T.

AU - Lilja, Jari J.

AU - Backman, Janne T.

AU - Soukhova, Nadia

AU - Neuvonen, Pertti J.

AU - Flockhart, David A.

PY - 2001

Y1 - 2001

N2 - 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 (4.8plusmn;3 h). Compared with the water treated group, grapefruit juice significantly increased the mean Cmax of (-)-cisapride from 30plusmn;13.6-55.5plusmn;18 ng ml-1 (95% CI on mean difference, -33,-17; P=0.00005) and of (+)-cisapride from 10.5plusmn;3.4 to 18.4plusmn;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 201plusmn;161 to 521.6plusmn;303 ng ml-1 h (95% CI on mean difference, -439, -202; P=0.0002) and that of (+)-cisapride from 70plusmn;51.5 to 170plusmn;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; P1/2 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-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.

AB - 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 (4.8plusmn;3 h). Compared with the water treated group, grapefruit juice significantly increased the mean Cmax of (-)-cisapride from 30plusmn;13.6-55.5plusmn;18 ng ml-1 (95% CI on mean difference, -33,-17; P=0.00005) and of (+)-cisapride from 10.5plusmn;3.4 to 18.4plusmn;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 201plusmn;161 to 521.6plusmn;303 ng ml-1 h (95% CI on mean difference, -439, -202; P=0.0002) and that of (+)-cisapride from 70plusmn;51.5 to 170plusmn;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; P1/2 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-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.

KW - Cisapride

KW - Grapefruit juice

KW - Pharmacokinetics

KW - Stereoselectivity

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