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Chapter 6 132 release formulations of peppermint oil, produced by different manufacturers, produced from a different harvest of mint leaves, were used. L-Menthol concentrations in peppermint oil are known to vary between 30% and 55%. 32 When taken orally, L- menthol is rapidly metabolized to menthol-glucuronide, which can be measured successfully in blood-plasma by Gas Chromatography Mass Spectrometry. 35 Consequently, the menthol-glucuronide is excreted in urine. 9 The menthol-glucuronide concentration was not measured directly in the small intestine and colon because of the practical difficulties of an ileocolonic intubation. Unlike other studies that have compared peppermint oil formulations, however, we think pharmacokinetic parameters could be compared more reliably as both formulations used here contained the same amount of L-menthol; the ileocolonic release peppermint oil capsules were created by overencapsulation of small-intestinal release peppermint oil capsules from the same manufacturer. 19 We presume that the difference in T max found between the small-intestinal and ileocolonic release peppermint oil reflects the longer transit needed to reach the colon. It should be also noted that our study showed large interquartile ranges in plasma menthol-glucuronide levels, indicating high inter-subject variability. Measures taken to decrease any variability were standardized meals and snacks, an overnight fast, and the complete abstinence from caffeine, alcohol, smoking, and medicines affecting gastrointestinal function in a predefined period prior to drug administration. The variability found can therefore probably be explained by normal biological variation in gastrointestinal transit times, and polymorphic variation in cytochromes P450 (CYP) enzymes, which are known to facilitate L-menthol metabolism. 37-40 The delayed peak concentration of the novel ileocolonic release peppermint oil and, thus, more distal exposure to peppermint oil are not only expected to increase therapeutic efficacy, but it is also expected to lead to a different and possibly milder spectrum of adverse events, as there is less upper gastrointestinal but more distal gastrointestinal exposure to peppermint oil. This pilot study has examined possible adverse events after only a single dose of peppermint oil and was not powered to draw any conclusions regarding adverse events since it only included eight volunteers. In addition to evaluating short term adverse events, future studies should also evaluate the long-term adverse events occurring when peppermint oil capsules of 182 mg are taken three times daily, the dosage identified by previous studies as being effective in IBS patients and the industry norm. 20,22,24,41