CYP1A2, caffeine metabolism

Fuhr, U., Klittich, K. et al. (1993). Inhibitory effect of grapefruit juice and its bitter principal, naringenin, on CYP1A2 dependent metabolism of caffeine in man. Br. J. Clin. Pharmacol., 35(4), 431-6. 

The phenotype for human CYP1A2 activity can be conveniently measured in vivo using caffeine as a probe drug and measuring urinary or salivary metabolite profiles. The caffeine metabolic ratio is increased in populations of smokers (31,92) and wide ranges of CYP1A2 activity have been measured in many different human studies (Table 2). 

Welfare MR, Aitkin M, Bassendine MF, Daly AK. Detailed modelling of caffeine metabolism and examination of the CYP1A2 gene lack of a polymorphism in CYP1A2 in Caucasians [published erratum appears in Pharmacogenetics 1999 Dec 9(6) 782]. Pharmacogenetics 1999 9 367-375. 

The relative safety of caffeine has lead to its widespread use as an in vivo probe for CYP1A2 activity in man. The primary route of caffeine metabolism is via N-demethylation to paraxanthine, theophylline, and theobromine. The major route of caffeine clearance in man is to paraxanthine (57). The N-3-demethylation of caffeine to paraxanthine has been shown to be mediated by CYP1A2 (58). However, paraxanthine is further metabolized to a number of different products, and as a consequence urinary metabolic ratios are often used to describe an individual CYP1A2 phenotype. 

Such approaches have been used successfully to demonstrate the induction of CYP1A2 by smoking (42). In addition, this study showed that oral contraceptives produce a small but significant inhibition of CYP1A2. Urinary metabolic ratios have also been used to show that oral AUC of clozapine was correlated with caffeine N-3-demethylation (59), a finding supported by some recent in vitro data, which has shown that clozapine N-demethylation is mediated by CYP1A2 (60). 

Sachse S, Bhambra U, Smith G et al. (2003) Polymorphisms in the cytochrome P4501A2 gene (CYP1A2) in colorectal cancer patients and control allele frequencies, linkage disequilibrium and influence on caffeine metabolism. Br J Clin Pharmacol 55 68-76... 

Fuchs P, Haefeli WE, Ledermann, Wenk M (1999) Xanthine oxidase inhibition by allopurinol affects the reliability of urinary caffeine metabolic ratios as markers for N-acetyltransferase2 and CYP1A2 activities. Eur J Clin Pharmacol 54 869-876... 

Caffeine 2. Chaste tree 3. Green tea 4. Plantain 1. Lithium 2. Phenothiazines (e.g. chlorpromazine, promazine, levomepromazine, pericyazine, pipotiazine, fluphenazine, perphenazine, trifluphenazine) 3. Clozapine L blood lithium levels with 1 clinical effects. 1 effects of phenothiazines Unknown mechanism (caffeine) Contains dopamine agonists (chaste tree) Induction of metabolizing enzymes (green tea may induce CYP1A2, which metabolizes clozapine) l absorption from the gut (plantain may l absorption of lithium) Be aware. Caffeine withdrawal may precipitate lithium toxicity, so avoid sudden caffeine withdrawal. Avoid concomitant use if possible... 

CYP1A2 participates in the metabohsm of both enoxacin and caffeine, and inhibition of caffeine metabolism by enoxacin can cause adverse effects (131). 

Oxidative metabolism of clozapine was found to correlate with caffeine metabolism (462)and is thus largely carried out by cytochrome P4501A2 (CYP1A2). No correlation with CYP2D6 polymorphism was found (461, 462). Several interaction studies of clozapine with SSRI antidepressants have been reported (465-469). Fluvoxamine increased plasma concentrations of clozapine in schizophrenic patients (463,464), presumably through inhibition of CYP1A2 catalyzed N-demethylation (465). Fluoxetine was found to increase the plasma concentrations of clozapine and its major metabolites, suggesting that this SSRI must interfere with pathways other than N-demethylation and N-dealkylation (466). Two other SSRIs, paroxetine (463) and citalopram (467), had no apparent effects on clozapine levels. 

Single-dose venlafaxine does not alter the single-dose pharmacokinetic profile of caffeine (metabolized by CYP1A2). 

Inhibits metabolizing enzymes (caffeine inhibits CYP1A2, which metabolizes clozapine). Inhibition of CYP by ginkgo t alpha-1 effects of risperidone. Valerian may worsen the sedative properties of haloperidol. Hops and phenothiazine have been associated with hyperthermia in dogs... 

Broccoli 500 g/day 12 days 16 2 female, 14 male Enhanced CYP1A2 — mediated by caffeine metabolism Kail et al., 1996 ... 

There is no accumulation of caffeine or its metabolites in the body and less than 2% of caffeine is excreted imchanged in the urine. Some rate-limiting steps in caffeine metabolism, particularly demethy-lation into paraxanthine that is selectively catalyzed by CYP1A2, determine the rate of caffeine clearance and the dose-dependent pharmacokinetics in humans. 

Walton et al. (2001a) examined data for compounds eliminated by the cytochrome P450 isoenzymes CYP1A2 in humans. Absorption, bioavailabihty, and route of excretion were generally similar between humans and the test species for each of the substances (caffeine, paraxanthine, theobromine, and theophylline). However, interspecies differences in the route of metabolism, and the enzymes involved in this process, were identified. The magnitude of difference in the internal dose, between species, showed that values for the mouse (10.6) and rat (5.4) exceeded the fourfold default factor for toxicokinetics, whereas the rabbit (2.6) and the dog (1.6) were below this value. 

Polybrominated Biphenyls. A recent study has used caffeine as a potential tool to characterize exposure and/or effect of PBBs (Lambert et al. 1990). In this test, caffeine is used as a metabolic probe of cytochrome P-450 isozymes activity from the CYPIA family, which in animals is significantly induced by PBBs (Safe 1984). Tire caffeine breath test (CBT) is primarily useful for detecting induction of CYP1A2 activity in human liver, and for that reason, it also has been used as a marker for exposure to PCBs, CDDs, and CDFs (Lambert et al. 1992). A volunteer population of 50 Michigan subjects with previously high serum PBB levels and 50 with undetectable or low serum levels was compared to a control population not exposed to PBBs (Lambert et al. 1992). Two tests were conducted, the CYP1A2-dependent caffeine... 

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