Abstract
This open-label, randomized, two-way crossover study compared the relative heterogeneity in systemic availability of oral ondansetron and granisetron. It was conducted in 10 healthy male and 10 healthy female subjects aged 18 to 50 years. Following an overnight fast, each subject received 8 mg ondansetron and 1 mg granisetron. Treatments were separated by 7 days. Blood samples for drug assay were collected over a period of 36 h and variability in pharmacokinetic parameter estimates were assessed following standardization by their respective means. Granisetron showed significantly more variability than ondansetron in the three primary endpoints of the area under the curve extrapolated to infinite time, the area under the curve to the last quantifiable time point, and maximal concentration (p = .0032, .0037, and .0042, respectively). In one subject, concentrations of granisetron were detectable but below the lower limit of quantitation at any time point. The impact this variability may have on therapeutic efficacy is not clear. An apparent bimodal distribution in granisetron AUC infinite, which appeared to be related to smoking was observed. Because granisetron has been reported to be metabolized primarily by the cytochrome P-450 (CYP) 3A isozyme family in humans, it is possible that cigarette smoke could be an inducer of CYP3A or that CYP1A2, also implicated in the metabolism of granisetron and known to be induced by smoking, is more important in the biotransformation of granisetron than previously thought.
Footnotes
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Send reprint requests to: J. L. Palmer, Clinical Pharmacology Division, Glaxo Wellcome Research and Development, Greenford Road, Greenford, Middlesex UB6 0HE, United Kingdom. E-mail jlp4823{at}glaxowellcome.co.uk
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↵1 Abbreviations used are: CYP, cytochrome P-450;AUC∞, area under the curve extrapolated to infinite time; AUClast, area under the curve to the last quantifiable time point; and Cmax, maximal concentration; LOQ, limit of quantitation.
- Received January 16, 1998.
- Accepted June 18, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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