Mechanistic pharmacokinetic modelling of ephedrine, norephedrine and caffeine in healthy subjects

Aim The combination of ephedrine and caffeine has been used in herbal products for weight loss and athletic performance-enhancement, but the pharmacokinetic profiles of these compounds have not been well characterized. This study aimed to develop a mechanistic model describing ephedrine, norephedrine, and caffeine pharmacokinetics and their interactions in healthy subjects. Methods The pharmacokinetic model was developed based on the simultaneous modelling using plasma samples gathered from two clinical trials. The treatments consisted of single-doses of pharmaceutical caffeine and ephedrine, given alone or together, and an herbal formulation containing both caffeine and ephedrine. We used a mixed-effect statistical model and the program NONMEM to take account of intersubject variability. Results Three hundred and seventy-nine ephedrine, 352 norephedrine, 417 caffeine plasma concentrations and 40 ephedrine urine concentrations were obtained from 24 subjects. A one-compartment model with first-order absorption described the caffeine data. Caffeine clearance was 0.083 l min(-1) (CV 38%) and decreased to 0.038 l min(-1) in presence of oral contraceptive therapy, its volume of distribution was 38.6 l (CV 20%) and its absorption rate constant was 0.064 l min(-1) (CV 50%). A four-compartment model described the pharmocokinetics of ephedrine and norephedrine. Ephedrine was eliminated mostly renally, with a clearance of 0.34 l min(-1) (CV 11%), and a volume of distribution of 181 l (CV 19%). Nonlinearity in the conversion of ephedrine to norephedrine was observed. Different models showed that the simultaneous administration of caffeine, or the amount of caffeine in the absorption compartment, was associated with a slower rate of absorption of ephedrine. A 32% greater relative bioavailability of herbal compared with pharmaceutical ephedrine administration was observed. Conclusions We describe a mechanistic model for ephedrine, norephedrine and caffeine pharmacokinetics and their interactions. The relative bioavailability of ephedrine differed between the herbal supplement compared with the pharmaceutical formulation. Concomitant ingestion of caffeine slowed the absorption rate of ephedrine, which is mainly related to the amount of the former in the absorption compartment. A saturable process appears to be involved in the metabolism of ephedrine to norephedrine.