Effect of grapefruit juice (GFJ) on the stereo-selective pharmacokinetics (PK) of cisapride (CIS) and cardiac qtc interval in healthy volunteers

Z. Desta, K. T. Kivistö, J. J. Lilja, J. T. Backman, P. J. Neuvonen, N. Soukhova, D. A. Flockhart

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Abstract

In a randomized, cross over design, 10 healthy volunteers were administered 200ml double strength GFJ 3 times a day for 2 days or water (W) as control. On the 3rd day, each subject ingested a single 10mg dose of racemic CIS tablet with 200ml GFJ or W. The same amount of GFJ or W was given 1/2 and 1 1/2 hour after CIS dosing. EKGs and blood were sampled before and for 32 h after CIS administration. Plasma (+)-and (-)-CIS were measured by chiral HPLC. (-)-CIS (+)-CIS Tmax Cmax AUL0-∞ Tmax Cmax AUC0-∞ (h) (ng/ml) (ng/ml*h) (h) (ng/ml) (ng/ml*h) CIS+W 1.4±0.4 30±14 201±161 1.8±0.5 11 ±3 1 52±7 1 CIS+GFJ 2.8±1*56±18 2 522±303 2 2.9±1.6*18± 6 3 170±91 3 p<0.05. 1 Cmax and AUC[(+)-vs(-)-CIS in W group];*GFJ vs W; 2 Cmax and AUC of (-)-CIS (GFJ vs W); 3 Cmax and AUC of (+)-CIS (GFJ vs W). CIS PK exhibit marked stereoselectivity. GFJ significantly increased the mean Cmax and AUC0-∞ of both enantiomers, probably through inhibition of CYP3A in the intestine, but had no effect on the mean QTc interval. Provided the two enantiomers elicit different cardiac and prokinetic responses, the plasma concentrations of individual enantiomer may better predict the safety and efficacy of CIS than those of racemic.

Original languageEnglish (US)
Pages (from-to)P82
JournalClinical Pharmacology and Therapeutics
Volume69
Issue number2
StatePublished - Jan 1 2001

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ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

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