Caffeine metabolism inhibitors

Cyt 1A2 metabolizes clozapine common substrates - amitriptyline, clomipramine, propranolol, theophylline, warfarin, caffeine. Common inhibitors - fluvoxamine, paroxetine. 

These pyrolysis products were also found in roasted tea and brandy-type alcoholic beverages (Sugimura and Sato, 1983). In addition, as a result of ethanol metabolism, mutagenic acetaldehyde is formed, while in coffee and tea caffeine, an inhibitor of DNA repair synthesis is present and may also contribute to cancer risk. 

Table 15-1], Amphetamines and caffeine (a melhylxanthine alkaloid) stimulate catecholamine release, and tricyclic antidepressants and cocaine inhibit the uptake of released catecholamine neurotransmitters. Fluoroacetate is a metabolic inhibitor of aconitase in the tricarboxylic acid (TCA) cycle and its cardiac effects are the result of acute severe energy deficit in the myocardium.

Clozapine is principally metabolized to N -desmethylclozapine (norclozapine). It is also metabolized to and n-oxide, other hydroxyl metabolites, and a protein-reactive metabolite. The n-oxide can be converted back to clozapine. The enzyme responsible for the metabolism of clozapine to norclozapine is the cytochrome P450 1A2 enzyme (325). This is consistent with a study showing that caffeine, a marker for 1A2, is cleared in relationship to the conversion of clozapine to norclozapine ( 326). Discontinuation of coffee intake can decrease the clozapine plasma levels by more than 50%, and increasing caffeine intake can produce a reemergence of the side effects (e.g., drowsiness, excess salivation). Additionally, smoking, which induces 1A2, lowers clozapine plasma levels. Fluvoxamine, an inhibitor of 1A2, dramatically increases plasma levels, and on occasion, adverse effects are seen ( 327). This phenomenon can lead to clozapine intoxication in patients on high doses of fluvoxamine. 

The interaction between the quinolone antibacterials and CYP1A2 has been studied in some depth for enoxacin and pefloxacin. Both compounds have been shown to inhibit CYPlA2-mediated metabolism of caffeine in vitro (49). This in vitro inhibition translated into a twofold decrease in caffeine clearance by pefloxacin and a sixfold decrease in clearance by enoxacin (50). Because pefloxacin undergoes N-demethylation to norfloxacin (51) and norfloxacin is much more potent as an inhibitor than pefloxacin (50), the observed in vivo interaction seen for pefloxacin may, in part, be due to norfloxacin. Many other quinolone antibacterial agents have been investigated for their interaction with theophylline, and ciprofloxacin has also been shown to have notable inhibitory effects (52). 

Rasmussen BB, Nielsen TL, Brosen K. Fluvoxamine is a potent inhibitor of the metabolism of caffeine in vitro. Pharmacol Toxicol 1998 83 240-245. 

The urinary caffeine test is not based on assays of specific substrates and products of NAT2 ( including other metabolism pathways involving at least xanthine-oxidases), and is affected by diet habits, xanthine-oxidase inhibitors such as allopurinol (Fuchs 1999), or other drugs (Klebovitch 1995). NAT activities are affected by anti-inflammatory drugs. Of note, acetominophen is an inhibitor of NAT2 in vivo (Rothen 1998). 

Rothen JP, Haefeli WE, Meyer UA et al. (1998) Acetominophen is an inhibitor of hepatic N-acetyltransferase 2 in vitro and in vivo. Pharmacogenetics 8 553-559 Tang BK, Kadar D, Qian L et al. (1991) Caffeine as a metabolic probe validation of its use for acetylator phenotyping. Clin Pharmacol Ther 49 648-657... 

Given concurrently with TCAs they may cause serious adverse effects. Fluvoxamine may raise levels of caffeine and theophylline, and fluoxetine can interfere with the metabolism of clozapine, cyclosporin, and tefenadine (18, 46). SSWs should never be given with MAO inhibitors because a fatal "serotonin syndrome" has been reported with fluoxetine in this combination (18). 

A minor metabolite of theophylline in adults, caffeine has been shown to accumulate to significant concentrations in neonates. Caffeine itself is an effective inhibitor of apnea, which may explain the lower therapeutic concentration required for control of neonatal apnea. Therapy with caffeine alone has also been demonstrated as effective in the treatment of neonatal apnea it is gaining popularity because of caffeine s long half-life in neonates (>30 hours). Caffeine is metabolized by CyP 1A2 this enzyme is not active in neonates. The optimal therapeutic concentration of caffeine in this situation ranges from 8 to 14pg/mL. Caffeine is measured by HPLC or immunoassay. 

Citric acid, found in citrus fruits, is listed as an inhibitor, and also occurs as a reaction intermediate in the metabolic tricarboxylic acid or dtric acid cycle. Ethanol or ethyl alcohol makes an unexpected appearance as an inhibitor, as does glycerol. The ubiquitous alkaloid ingredient of coffee, better known as caffeine, is listed as an inhibitor (in fact, coffee enemas are sometimes used in folkloric cancer treatments). Creatine, a nitrogenous compound found naturally in the body, is an inhibitor, and is a known anticancer agent, for example, as used with urea in a nuxture called Carbatine. 

Fluoroquinolone antibiotic bactericidal inhibitor of topoisomerases active against E coli, H influenzae, Campylobacter, enterobacter, pseudomonas, shigeUa. Tox CNS dysfunction, GI distress, superinfection, collagen dysfunction (avoid in children and pregnant women). Interactions inhibits metabolism of caffeine, theophylline, warfarin. 

In contrast to caffeine, propafenone coadministration significantly reduced the metabolism of both enantiomers of mexiletine in EMs [132]. However, it did not have a significant effect on the pharmacokinetics of mexiletine enantiomers in PMs. In fact, after coadministration of propafenone to EMs, the plasma concentration-time profiles and pharmacokinetics of mexiletine enantiomers in these subjects were not distinguishable from those in PMs [132]. These results are in agreement with the inhibitory effects of propafenone on the CYP2D6 pathway and are similar to those obtained with quinidine, another CYP2D6 inhibitor (Table 13). 

Caffeine is a eompetitive inhibitor of the cytochrome P450 isoenzyme CYP1A2, which is one of the major isoenzymes involved in the metabolism of caffeine. Consequently clozapine serum levels and effects... 

The changes seen in some studies probably occurred because cimetidine, a well-known non-specific enzyme inhibitor reduced the metabolism of caffeine by the liver, resulting in its accumulation in the body. 

Theobromine is an alkaloid used in medicine much like caffeine, due to the similar properties of these two alkaloids. Theobromine stimulates the CNS and increases blood flow. Older studies mention that the theobromine in cocoa powder stimulated growth in rats and no evidence of carcinogenicity was found. Moreover, it was also stated that theobromine stimulates clostridium-perfringens enterotoxin formation. Rasouli and Zahraie observe that theobromine is also well known as an adenosine 3, 5 -cyclic monophosphate (cAMP) inhibitor and participates in the regulation of intra-hepatic metabolism of very low density lipoproteins. 

---