Verlängerung der QT-Zeit
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Coffein ist in Form z.B. von Kaffee oder Tee ein Genussmittel, das eine anregende Wirkung besitzt. Es wird als Coffeincitrat bei Frühgeborenen eingesetzt, um die Nachreifung der Lunge zu fördern und Atemstörungen zu behandeln. Ausserdem ist es Bestandteil einiger Antihistaminika- Präparate, um die müde machende Wirkung dieser zu kompensieren. Coffein ist ein Stimulans des Zentralnervensystems (ZNS) und chemisch ein Xanthinalkaloid. Es ist chemisch mit den DNA- und RNA- Bausteinen Adenin- und Guanin verwandt und kommt in verschiedenen Pflanzen vor (z.B. Kaffeestrauch, Teestrauch, Guaraná, Mate-Strauch oder Kolanuss). Als Analogon von Adenosin blockiert Koffein dessen Rezeptoren im Gehirn und verhindert seine beruhigende Wirkung. Zudem greift es in den Energiestoffwechsel der Zellen ein (second messenger cAMP-System). So stimuliert Coffein das Zentralnervensystem und führt zu mehr Wachheit und erhöhter Konzentrationsfähigkeit, erhöht Puls und Blutdruck, fördert die Diurese (Harnausscheidung), erweitert die Bronchien und steigert die Darmbewegungen. 1819 isolierte der deutsche Apotheker und Chemiker Friedlieb Ferdinand Runge angeblich auf Anregung von Johann Wolfgang Goethe hin erstmals reines Koffein aus Kaffeebohnen.
Die Warnhinweise werden für die Kombination mehrerer Wirkstoffe überprüft. Für die einzelnen Substanzen konsultieren Sie bitte die entsprechende Fachinfo.
Da nur Coffein ohne weitere Substanzen eingeben wurde, können keine pharmakokinetischen Interaktionen detektiert werden.
Für die Berechnung der individuellen Expositionsveränderungen durch die Wechselwirkungen werden als Ausgangsbasis die pharmakokinetischen Parameter der durchschnittlichen Population verwendet.
Coffein hat eine hohe orale Bioverfügbarkeit [ F ] von 92%, weshalb die maximalen Plasmaspiegel [ Cmax ] sich bei einer Interaktion tendentiell wenig verändern. Die terminale Halbwertszeit [ t12 ] beträgt 11.91 Stunden und konstante Plasmaspiegel [ Css ] werden ungefähr nach 47.64 Stunden erreicht. Die Proteinbindung [ Pb ] ist mit 30.5% eher schwach und das Verteilungsvolumen [ Vd ] liegt mit 36 Liter im mittleren Bereich. da die Substanz eine tiefe hepatische Extraktionsrate von 0.07 besitzt, kann eine Verdrängung aus der Proteinbindung [Pb] im Rahmen einer Interaktion die Exposition erhöhen. Die Metabolisierung findet vor allem über CYP1A2 statt.
|Serotonerge Effekte a||0||Ø|
Bewertung: Gemäss unseren Erkenntnissen erhöht Coffein nicht die serotonerge Aktivität.
|Kiesel & Durán b||0||Ø|
Bewertung: Gemäss unseren Erkenntnisse erhöht Coffein nicht die anticholinerge Aktivität.
Verlängerung der QT-Zeit
Für Coffein ist uns kein QT-Zeit verlängerndes Potential bekannt.
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Abstract: Six healthy volunteers received a single caffeine dose after pretreatment with norfloxacin, pipemidic acid, or placebo in a crossover, randomized, single-blind clinical trial. Quinolones altered the pharmacokinetics of caffeine, with a significant increase in the AUCs and a decrease in plasma clearance. The elimination half-life increased significantly with pipemidic acid. The apparent volume of distribution, mean renal clearance, and time to reach maximum caffeine concentrations remained unaltered. There was a decline in caffeine metabolite levels in the 24-hour urine samples for both quinolone treatments, suggesting that pipemidic acid and, to a lesser degree, norfloxacin inhibit metabolism of the N-demethylation pathways of caffeine. The practical consequence of this observation could be caffeine accumulation during repeated intake of coffee. In two additional healthy volunteers under a controlled multiple-dose regimen of caffeine ingestion, administration of pipemidic acid for 2 days caused a fourfold increase in the plasma concentrations of caffeine.
Abstract: In an acute experiment in healthy volunteers and in patients under long-term treatment for cardiac arrhythmias, mexiletine inhibits caffeine elimination by about 50%. The clearance of mexiletine is not influenced by caffeine. Some side effects of mexiletine may possibly at least partially be attributable to a retention of caffeine.
Abstract: Five subjects who participated in an earlier study (Lelo et al., 1986b) of the comparative pharmacokinetics of caffeine (CA) and its primary monodemethylated metabolites paraxanthine (PX), theobromine (TB) and theophylline (TP) were administered CA to steady-state. Using areas under the plasma concentration-time curves for each of the dimethylxanthines derived from CA in the steady-state study and individual plasma clearances of PX, TB and TP determined in the previous study, the fractional conversion of CA to PX, TB and TP and the individual partial clearances of CA have been defined. The mean (+/- s.d.) fractional conversion of CA to PX, TB and TP was 79.6 +/- 21.0%, 10.8 +/- 2.4% and 3.7 +/- 1.3%, respectively. When only demethylation pathways are considered PX, TB and TP accounted for 83.9 +/- 5.4%, 12.1 +/- 4.1% and 4.0 +/- 1.4%, respectively of the CA demethylations. The mean partial clearance of CA to PX was approximately 8-fold and 23-fold greater than those to TB and TP respectively. These data confirm earlier reports that PX is the major metabolite of CA in humans but suggest that PX formation is quantitatively more important than previously believed.
Abstract: The disposition of caffeine and its metabolites was studied in six healthy subjects by use of sensitive and specific assays. The primary degradation of caffeine in man was found to be N-demethylation and/or ring oxidation to theophylline, paraxanthine, theobromine and 1,3,7-trimethyluric acid. These compounds were further degraded to dimethylated uric acids, monomethylxanthines and monomethyluric acids. About 3 and 6% of the drug was converted to theophylline and theobromine, respectively. The elimination of paraxanthine after its formation did not follow linear kinetics. A large urine recovery of 1-methylxanthine after caffeine administration in comparison with the amount recovered after administration of theophylline suggests an inhibitory effect on the degradation of this metabolite by either caffeine itself or another metabolite of caffeine. Caffeine and its primary metabolites, dimethylxanthines, were extensively reabsorbed in the renal tubule. Their renal clearances were highly urine flow-dependent and their urinary excretion varied with urine output during the study. About 70% of the dose was recovered in the urine. Postulated degradation pathways of caffeine are discussed.
Abstract: In a controlled clinical trial, the elimination of caffeine was examined in 20 healthy women prior to and during one cycle of treatment with either of two oral contraceptive formulations, one containing 0.075 mg gestodene and 0.03 mg ethinylestradiol and one containing 0.125 mg levonorgestrel and 0.03 mg ethinylestradiol. In addition, caffeine clearance was determined 1 month after the last intake of the oral contraceptives. Compared with pretreatment values, the clearance of caffeine was reduced by about 54% and 55% after one treatment cycle with gestodene- and the levonorgestrel-containing oral contraceptive, respectively. Other pharmacokinetic parameters of caffeine, such as tmax and Cmax, were not affected. Clearance values returned to pretreatment values 1 month after the last administration of the oral contraceptives. There was no difference in the reduction of caffeine clearance between contraceptive formulations. A small, but significant difference in the AUC(0-24 h) values of ethinylestradiol was noted between both preparations. There was no correlation between the AUC(model) values of caffeine and the AUC(0-24 h) values of ethinylestradiol. In the present study, a somewhat more pronounced effect on the elimination of caffeine was observed than in previous investigations, where several contraceptive steroids were administered only for a period of 2 weeks.
Abstract: BACKGROUND AND OBJECTIVES: Pefloxacin is reported to cause clinically relevant inhibition of theophylline metabolism in vivo, but in vitro pefloxacin was only a weak inhibitor of the cytochrome P450 CYP1A2, mediating main theophylline biotransformation. We therefore further characterized the interaction between pefloxacin and CYP1A2. METHODS: A randomized 3-period change-over study was conducted in 12 healthy young volunteers on the steady-state interactions between pefloxacin or enoxacin (400 mg twice a day) with caffeine (183 mg once daily), a validated marker of CYP1A2. Caffeine pharmacokinetics were estimated after its fifth dose. Studies in human liver microsomes were carried out to measure the effect of pefloxacin and norfloxacin on caffeine 3-demethylation, an in vitro CYP1A2 probe, and to identify the enzyme(s) that mediate pefloxacin N-4'-demethylation with selective inhibitors. RESULTS: For the in vivo study, ANOVA-based point estimates (90% confidence intervals [CI]) for the ratios of caffeine pharmacokinetics with and without pefloxacin coadministration were 1.11 for maximal steadystate plasma concentrations (Cmax,ss; 90% CI, 0.99 to 1.26), 0.53 for total clearance (CLt,ss; 90% CI, 0.49 to 0.58), and 1.04 for the beta-phase distribution volume (Vdbeta; 90% CI, 0.96 to 1.13). The values for enoxacin were 1.99 for Cmax,ss (90% CI, 1.77 to 2.23), 0.17 for CLt,ss (90% CI, 0.16 to 0.19), and 1.01 for Vdbeta (90% CI, 0.90 to 1.13). Thus pefloxacin caused a 2-fold decrease in caffeine clearance, and enoxacin caused a 6-fold decrease in caffeine clearance. In vitro, norfloxacin and pefloxacin competitively inhibited CYP1A2, with inhibition constant (Ki) values of 0.1 and 1 mmol/L, respectively, and CYP1A2 was the only enzyme with a relevant contribution (approximately 50%) to pefloxacin N-4'-demethylation. CONCLUSIONS: Enoxacin and to a lesser extent pefloxacin may cause clinically relevant interactions with further CYP1A2 substrates. The data suggest that the pefloxacin interaction is partly mediated by its major metabolite norfloxacin.
Abstract: Caffeine from dietary sources (mainly coffee, tea and soft drinks) is the most frequently and widely consumed CNS stimulant in the world today. Because of its enormous popularity, the consumption of caffeine is generally thought to be safe and long term caffeine intake may be disregarded as a medical problem. However, it is clear that this compound has many of the features usually associated with a drug of abuse. Furthermore, physicians should be aware of the possible contribution of dietary caffeine to the presenting signs and symptoms of patients. The toxic effects of caffeine are extensions of their pharmacological effects. The most serious caffeine-related CNS effects include seizures and delirium. Other symptoms affecting the cardiovascular system range from moderate increases in heart rate to more severe cardiac arrhythmia. Although tolerance develops to many of the pharmacological effects of caffeine, tolerance may be overwhelmed by the nonlinear accumulation of caffeine when its metabolism becomes saturated. This might occur with high levels of consumption or as the result of a pharmacokinetic interaction between caffeine and over-the-counter or prescription medications. The polycyclic aromatic hydrocarbon-inducible cytochrome P450 (CYP) 1A2 participates in the metabolism of caffeine as well as of a number of clinically important drugs. A number of drugs, including certain selective serotonin reuptake inhibitors (particularly fluvoxamine), antiarrhythmics (mexiletine), antipsychotics (clozapine), psoralens, idrocilamide and phenylpropanolamine, bronchodilators (furafylline and theophylline) and quinolones (enoxacin), have been reported to be potent inhibitors of this isoenzyme. This has important clinical implications, since drugs that are metabolised by, or bind to, the same CYP enzyme have a high potential for pharmacokinetic interactions due to inhibition of drug metabolism. Thus, pharmacokinetic interactions at the CYP1A2 enzyme level may cause toxic effects during concomitant administration of caffeine and certain drugs used for cardiovascular, CNS (an excessive dietary intake of caffeine has also been observed in psychiatric patients), gastrointestinal, infectious, respiratory and skin disorders. Unless a lack of interaction has already been demonstrated for the potentially interacting drug, dietary caffeine intake should be considered when planning, or assessing response to, drug therapy. Some of the reported interactions of caffeine, irrespective of clinical relevance, might inadvertently cause athletes to exceed the urinary caffeine concentration limit set by sports authorities at 12 mg/L. Finally, caffeine is a useful and reliable probe drug for the assessment of CYP1A2 activity, which is of considerable interest for metabolic studies in human populations.
Abstract: PURPOSE: Oltipraz is currently undergoing clinical evaluation as a cancer chemopreventive agent, especially with respect to aflatoxin-associated hepatocarcinogenesis. The agent's ability to induce phase II xenobiotic enzymes that detoxify the ultimate carcinogen formed in vivo is thought to be an important mechanism by which disease risk may be attenuated. However, an additional mechanism could be a reduction in the activation of environmental procarcinogens by certain cytochrome P450 (CYP) isoforms. This hypothesis was tested with respect to CYP1A2, by using the clearance of caffeine by N-demethylation as a phenotypic trait measurement of the isoform's catalytic activity. METHODS: Subjects received a single oral dose of caffeine (200 mg) on five separate occasions: on the day prior to oltipraz administration (day 0), 2 h after the first (day 1) of eight daily oral doses of oltipraz (125 mg) and 2 h after the last dose (day 8). In addition, CYP1A2 activity was also measured 2 and 14 days (days 10 and 22, respectively) after discontinuation of oltipraz administration. Plasma concentrations of caffeine and its N-demethylated metabolite, paraxanthine, over 24 h after drug administration, were determined by HPLC. RESULTS: A single 125-mg dose of oltipraz markedly reduced CYP1A2 activity by 75 +/- 13% in nine healthy subjects, resulting in a higher caffeine plasma level and prolongation of the in vivo probe's elimination half-life. Daily administration of 125 mg oltipraz for 8 days resulted in further inhibition so that only 19 +/- 13% of the original baseline level of activity was present. However, 2 days after discontinuation of oltipraz treatment, CYP1A2 activity had returned to 66 +/- 33% of its original level and complete recovery was achieved within 14 days of the chemopreventive agent being stopped. CONCLUSIONS: These results demonstrate that oltipraz is a potent, in vivo inhibitor of CYP1A2 in humans and, because this isoform is importantly involved in procarcinogen activation, they also indicate that such inhibition probably contributes to oltipraz's cancer-chemopreventive effect. In addition, the findings also suggest the likelihood of significant drug interactions between oltipraz and drugs whose metabolism is mediated by CYP1A2.
Abstract: Children's risks can differ from those in adults for numerous reasons, one being differences in the pharmacokinetic handling of chemicals. Immature metabolism and a variety of other factors in neonates can affect chemical disposition and clearance. These factors can be incorporated into physiologically based pharmacokinetic (PBPK) models that simulate the fate of environmental toxicants in both children and adults. PBPK models are most informative when supported by empirical data, but typically pediatric pharmacokinetic data for toxicants are not available. In contrast, pharmacokinetic data in children are readily available for therapeutic drugs. The current analysis utilizes data for caffeine and theophylline, closely related xanthines that are both cytochrome P-450 (CYP) 1A2 substrates, in developing PBPK models for neonates and adults. Model development involved scale-up of in vitro metabolic parameters to whole liver and adjusting metabolic function for the ontological pattern of CYP1A2 and other CYPs. Model runs were able to simulate the large differences in half-life and clearance between neonates and adults. Further, the models were able to reproduce the faster metabolic clearance of theophylline relative to caffeine in neonates. This differential between xanthines was found to be due primarily to an extra metabolic pathway available to theophylline, back-methylation to caffeine, that is not available to caffeine itself. This pathway is not observed in adults exemplifying the importance of secondary or novel routes of metabolism in the immature liver. Greater CYP2E1 metabolism of theophylline relative to caffeine in neonates also occurs. Neonatal PBPK models developed for these drugs may be adapted to other CYP1A2 substrates (e.g., arylamine toxicants). A stepwise approach for modeling environmental toxicants in children is proposed.
Abstract: OBJECTIVE: To investigate the likelihood of artemisinin and thiabendazole causing pharmacokinetic interactions involving cytochrome P450 (CYP1A2) in humans given their potent inhibitory effects on the isoform in vitro. METHODS: Ten healthy volunteers received caffeine (136.5 mg), and after a washout period of 48 h, the volunteers were given a caffeine tablet (136.5 mg) together with thiabendazole (500 mg). After an additional 14 days, the volunteers received caffeine together with artemisinin (500 mg). After each treatment, plasma was obtained up to 24 h post-dose. The plasma concentrations of the drugs were measured by HPLC with UV and MS detection. RESULTS: Using the ratio of paraxanthine to caffeine after 4 h as an indicator of CYP1A2 activity, thiabendazole and artemisinin inhibited 92 and 66%, respectively, of the enzyme activity in vivo. In addition, the pharmacokinetics of caffeine were altered in the presence of the drugs; increases in AUC(0-24) of 1.6-fold (P < 0.01) and 1.3-fold of caffeine in the presence of thiabendazole and artemisinin respectively were measured. The use of in vitro data to predict the effects of thiabendazole on the formation of paraxanthine yielded good results and underestimated the effects of artemisinin when total plasma concentrations were used. Corrections for protein binding resulted in underestimation of inhibitory effects on CYP1A2. CONCLUSIONS: Co-administration of thiabendazole or artemisinin with CYP1A2 substrates could result in clinically significant effects. Our results highlight the validity of in vitro data in predicting in vivo CYP inhibition. The formation of paraxanthine seems to be a better indicator of in vivo CYP1A2 activity than caffeine levels.