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Chapter 6 126 10 h 33,34 , no carry-over effects were anticipated as a result of the chosen wash-out period. Randomization, preparation, and labeling of the study medication were performed by an independent third party (Tiofarma BV, Oud Beijerland, The Netherlands). Half of the subjects received ileocolonic release capsules in the first test period (and small-intestinal release capsules in the second test period) and half of the subjects received small- intestinal release capsules in the first test period (and ileocolonic release capsules in the second test period), on the basis of on a randomized pre-selection using web-based randomization software. All capsules were packaged in identical, sealed containers and subject numbers and whether it was the first or second test day were mentioned on the label, ensuring allocation concealment. On both test days, subjects arrived at the hospital after fasting overnight. Upon arrival, the subject had an intravenous catheter inserted for blood sampling. Prior to the administration of the peppermint oil capsule, several baseline measurements were taken; a venous blood sample was taken to determine baseline plasma menthol- glucuronide, an evaluation of baseline side effects was conducted and blood pressure/heart rate were measured. At t=0, the study medication was administered with a 200 mL glass of water. Consequently, at t= 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, and 24 h, venous blood sampling, side effect evaluation and blood pressure/heart rate measurements were repeated. Two hours after capsule intake, a standardized breakfast was provided (two sandwiches with cheese and cucumber, glass of milk, 384 calories in total). Lunch and dinner were subsequently provided at t=6 h and t=10 h after capsule intake, respectively. The last measurement before midnight took place at t=14 h, after which the intravenous cannula was removed and the subject was allowed to return home. Participants returned to the hospital for the last measurements at t=24 h. Throughout the complete study, volunteers were instructed to report any side effects. A telephonic evaluation took place between both test periods. Primary and secondary outcomes The primary outcome was T max : time to reach peak menthol-glucuronide concentration in plasma. The secondary outcomes were; T lag , time to reach a menthol-glucuronide concentration of 45 μg/L; AUC, Area Under the plasma concentration Curve; C max , peak menthol-glucuronide concentrations; T 1/2 , elimination half-life; side effects and tolerability, as determined by a side effect questionnaire and blood pressure/heart rate measurement.