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

Details

Serval ID
serval:BIB_FAC2AA7B0C9F
Type
Article: article from journal or magazin.
Collection
Publications
Title
Mechanistic pharmacokinetic modelling of ephedrine, norephedrine and caffeine in healthy subjects
Journal
British Journal of Clinical Pharmacology
Author(s)
Csajka  C., Haller  C. A., Benowitz  N. L., Verotta  D.
ISSN
0306-5251 (Print)
Publication state
Published
Issued date
03/2005
Volume
59
Number
3
Pages
335-45
Notes
Journal Article
Meta-Analysis
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S. --- Old month value: Mar
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.
Keywords
Administration, Oral Adult Biological Availability Caffeine/blood/*pharmacokinetics Clinical Trials Ephedrine/blood/*pharmacokinetics/urine Female Humans Male Phenylpropanolamine/blood/*pharmacokinetics
Pubmed
Web of science
Open Access
Yes
Create date
25/01/2008 10:48
Last modification date
20/08/2019 16:26
Usage data