A population and family study N-acetyltransferase using caffeine urinary metabolites

Bechtel, Y; Bonaïti‐Pellié, Catherine; Poisson, Nicole; Magnette, J.; Bechtel, P

doi:10.1038/clpt.1993.124

Cited by 50 publications

(32 citation statements)

References 3 publications

(3 reference statements)

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“…Caffeine is metabolized by several enzymes: it is demethylated by CYP enzymes, it forms uric acid metabolites via xanthine oxidase; and it is acetylated by N-acetyltransferase (Bechtel et al, 1993;Yuan et al, 2002). All three demethylation reactions are predominantly catalyzed by CYP1A2 and 2E1 (Yuan et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

Effects of rutaecarpine on the metabolism and urinary excretion of caffeine in rats

et al. 2011

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Although rutaecarpine, an alkaloid originally isolated from the unripe fruit of Evodia rutaecarpa, has been reported to reduce the systemic exposure of caffeine, the mechanism of this phenomenon is unclear. We investigated the microsomal enzyme activity using hepatic S-9 fraction and the plasma concentration-time profiles and urinary excretion of caffeine and its major metabolites after an oral administration of caffeine in the presence and absence of rutaecarpine in rats. Following oral administration of 80 mg/kg rutaecarpine for three consecutive days, caffeine (20 mg/kg) was given orally. Plasma and urine were collected serially for up to 24 h and the plasma and urine concentrations of caffeine and its metabolites were measured, and compared with those in control rats. The areas under the curve of both caffeine and its three major metabolites (paraxanthine, theophylline, and theobromine) were significantly reduced by rutaecarpine, indicating that caffeine was rapidly converted into the desmethylated metabolites, and that those were also quickly transformed into further metabolites via the hydroxyl metabolites due to the remarkable induction of CYP1A2 and 2E1. The significant induction of ethoxyresorufin O-deethylase, pentoxyresorufin O-depentylase, and p-nitrophenol hydroxylase strongly supported the decrease in caffeine and its major metabolites in plasma, as well as in urine. These results clearly suggest that rutaecarpine increases the metabolism of caffeine, theophylline, theobromine, and paraxanthine by inducing CYP1A2 and CYP2E1 in rats.

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Section: Discussionmentioning

confidence: 99%

Effects of rutaecarpine on the metabolism and urinary excretion of caffeine in rats

et al. 2011

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“…Reduced urinary excretion of these three metabolites in the previous oral study strongly supports the idea of further metabolism (Noh et al, 2011). In fact, caffeine would be metabolized by CYP enzymes (i.e., N-demethylation), xanthine oxidase (i.e., formation of uric acid metabolites) and/or N-acetyltransferase (i.e., N-acetylation) (Bechtel et al, 1993;Yuan et al, 2002). Among these, three demethylation reactions are predominantly catalyzed by CYP1A2 and 2E1 (Yuan et al, 2002).…”

Section: Discussionmentioning

confidence: 60%

Effects of Rutaecarpine on the Pharmacokinetics of Caffeine and Its Three Metabolites in Rats

Seo¹,

Noh²,

Kong³

et al. 2011

Biomolecules and Therapeutics

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Rutaecarpine, an alkaloid originally isolated from the unripe fruit of Evodia rutaecarpa, has been shown to be anti-infl ammatory. In the present study, a possible interaction between rutaecarpine and caffeine was investigated in male Sprague Dawley rats. Twenty four hr after the oral pretreatment with rutaecarpine at 80 mg/kg for three consecutive days, rats were treated intravenously with 10 mg/kg of caffeine. Compared with control rats, the pharmacokinetic parameters of caffeine in rutaecarpine-pretreated rats were signifi cantly changed, possibly due to the rapid metabolism. The production of three metabolites of caffeine (i.e., paraxanthine, theobromine and theophylline) was also signifi cantly changed in rats pretreated with rutaecarpine. The present results suggest that oral rutaecarpine would change the intravenous pharmacokinetic characteristics of caffeine.

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“…All demethylation reactions are predominantly catalysed by CYP1A2. This CYP isoform is exclusively responsible for the N3-demethylation of caffeine (formation of paraxanthine), but the N1-and N7-demethylation (formation of theobromine and theophylline) are also catalysed by CYP2E1 (Bechtel et al 1993;Yuan et al 2002). As all dimethylxanthines are predominantly formed through CYP1A2 catalysed reactions, the formation rate constants are expected to be correlated.…”

Section: Discussionmentioning

confidence: 99%

Population Pharmacokinetics of Caffeine and its Metabolites Theobromine, Paraxanthine and Theophylline after Inhalation in Combination with Diacetylmorphine

Zandvliet

Huitema

Jonge

et al. 2005

Basic Clin Pharma Tox

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Abstract:The stimulant effect of caffeine, as an additive in diacetylmorphine preparations for study purposes, may interfere with the pharmacodynamic effects of diacetylmorphine. In order to obtain insight into the pharmacology of caffeine after inhalation in heroin users, the pharmacokinetics of caffeine and its dimethylxanthine metabolites were studied. The objectives were to establish the population pharmacokinetics under these exceptional circumstances and to compare the results to published data regarding intravenous and oral administration in healthy volunteers. Diacetylmorphine preparations containing 100 mg of caffeine were used by 10 persons by inhalation. Plasma concentrations of caffeine, theobromine, paraxanthine and theophylline were measured by high performance liquid chromatography. Non-linear mixed effects modelling was used to estimate population pharmacokinetic parameters. The model was evaluated by the jack-knife procedure. Caffeine was rapidly and effectively absorbed after inhalation. Population pharmacokinetics of caffeine and its dimethylxanthine metabolites could adequately and simultaneously be described by a linear multi-compartment model. The volume of distribution for the central compartment was estimated to be 45.7 l and the apparent elimination rate constant of caffeine at 8 hr after inhalation was 0.150 hr ª1 for a typical individual. The bioavailability was approximately 60%. The presented model adequately describes the population pharmacokinetics of caffeine and its dimethylxanthine metabolites after inhalation of the caffeine sublimate of a 100 mg tablet. Validation proved the stability of the model. Pharmacokinetics of caffeine after inhalation and intravenous administration are to a large extent similar. The bioavailability of inhaled caffeine is approximately 60% in experienced smokers.

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A population and family study N-acetyltransferase using caffeine urinary metabolites

Cited by 50 publications

References 3 publications

Effects of rutaecarpine on the metabolism and urinary excretion of caffeine in rats

Effects of rutaecarpine on the metabolism and urinary excretion of caffeine in rats

Effects of Rutaecarpine on the Pharmacokinetics of Caffeine and Its Three Metabolites in Rats

Population Pharmacokinetics of Caffeine and its Metabolites Theobromine, Paraxanthine and Theophylline after Inhalation in Combination with Diacetylmorphine

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