Heterogeneity in systemic availability of ondansetron and granisetron following oral administration

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 ondan setron and 1 mg granisetron. Treatments were separated by 7 days. Blood sam ples for drug assay were collected over a period of 36 h and variability in pharmacokinetic parameter estimates were assessed following standardizatio n by their respective means, Granisetron showed significantly more variabil ity than ondansetron in the three primacy endpoints of the area under the c urve extrapolated to infinite time, the area under the curve to the last qu antifiable time point, and maximal concentration (p = .0032, .0037, and .00 42, respectively). In one subject, concentrations of granisetron were detec table but below the lower limit of quantitation at any time point. The impa ct this variability may have on therapeutic efficacy is not clear, An appar ent bimodal distribution in granisetron AUC infinite, which appeared to be related to smoking was observed, Because granisetron has been reported to b e 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 grani setron than previously thought.