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

Abstract

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.

Figure 1

Schematic representation of the compartmental model for caffeine, ephedrine and norephedrine pharmacokinetics, where A_x represents the amounts in the x compartment. A₁: caffeine absorption; A₂: plasma caffeine; A₃: ephedrine absorption; A₄: plasma ephedrine; A₅: plasma norephedrine; A₆: urine ephedrine. The curved arrow indicates the influence of caffeine on ephedrine absorption

Figure 2

Caffeine plasma concentrations (open circles) and population prediction in subjects taking (solid line) and not taking (dashed line) oral contraceptives. Upper panel: herbal administration of caffeine in eight subjects. Lower panel: pharmaceutical administration of caffeine in 16 subjects. The different population prediction lines are the consequences of different baseline caffeine concentrations prior to dosing

Figure 3

Plasma concentrations (open circles) and population prediction for norephedrine Upper panel: plasma concentrations for the eight subjects receiving herbal ephedrine. Lower panel: plasma concentrations for the 16 subjects receiving pharmaceutical ephedrine. Solid lines: predictions obtained by the final model assuming a nonlinear rate of conversion of ephedrine to norephedrine. Dotted lines: predictions obtained by the model assuming a constant rate of conversion from ephedrine to norephedrine

Figure 4

Plasma concentrations (open circles) and population prediction (solid line) for ephedrine. Upper panel: after intake of the herbal formulation. lower panel: after intake of the pharmaceutical formulation. Solid lines: predictions obtained by the final model (equation 10b). Dashed lines: predictions obtained without including the effect of caffeine on absorption. Dotted line: predictions assuming the same relative bioavailability for the two formulations