Explore The Feasibility Of Taking Myrtol Standardized Capsules After Meal From Pharmacokinetic Perspective

Objective:To explore the feasibility of taking Myrtol standardized capsules after meal from pharmacokinetic perspective.Methods:Firstly, a gas chromatography coupled with triple quadruples mass spectrometry assay was established and validated for determining plasma concentrations of eucalyptol. Secondly, a clinical pharmacokinetic study was performed. A single oral dose of 300 mg Myrtol standardized capsules was given to healthy male volunteers fasted or after meal in a randomized cross-over study. Eucalyptol was treated as a target component. The main pharmacokinetic parameters were calculated by the use of software DAS2.1.1 with non-compartmental method. The corresponding differences between dosing conditions (fasted or after meal) were investigated. Log-transformed Cmax, AUC(0-t) and AUC(0-∞) were tested for bioequivalence using ANOVA and Schuirmann two-one sided t-est. Tmax was analyzed by Wilcoxon’s test.Results:The assay was simple and rapid. The specificity, sensitivity, accuracy and precision all met the requirement for biopharmaceutical analysis. The pharmacokinetic parameters of dosing conditions (fasted or after meal) were as follows:rmax(3.7±1.1 vs 4.8±0.7h), Cmax(167.6±114.69 vs 518.89±314.47 ng·mL-1), T1/2(3.2±1.4 vs 2.6±0.7h), AUC0-t(584.91±369.90 vs 1271.61±605.82ng-h-mL-1) and AUC0-∞(690.36±467.26 vs 1458.02±720.21 ng·h·mL-1). There was statistically significant difference in Cmax, AUC(0-t) and AUC(o-∞) between the two dosing methods (P<0.05). Pharmacokinetic parameters of eucalyptol given in the fasted status in Chinese subjects were comparable to those in Germany population. The 90% CI for the ratio of Cmax (18.4%-64.7%) for the two dosing methods was beyond the China Food and Drug Administration (CFDA) acceptable range of 75%-133%. The 90% CI for the ratio of AUC0-t(28.9%-68.5%), and AUC0-∞, (31.1%～68.4%) values were also beyond the CFDA acceptable range of 80%-125%. In addition, significant difference was obtained in Tmax (P<0.05)Conclusion:Compared with dosing method at fasted condition, taking Myrtol standardized capsules after meal achieves a delayed absorption rate as well as a great increased absorption extent. The two dosing methods are not bioequivalent. The dosing method required by prescribing information for this formulation cannot be switched from an empty stomach condition to a feed status.Further clinical study is necessary to explore the clinical outcome of oral administration of Myrtol standardized capsules after or with meal.