Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: KEGG:D06103 (Theophylline)
 2,023 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Many drugs have been found to increase or decrease the clearance of theophylline, probably by interaction with one or more of the variants of the cytochrome P450 drug-metabolising system. Theophylline may be particularly susceptible to alteration of its clearance because of the particular form(s) of the P450 system involved, because its metabolism is saturable, and/or because 90% of its elimination is via metabolism. Its clearance has been found to be decreased (typically by around 25%, but often by far more) by erythromycin, troleandomycin (triacetyloleandomycin), roxithromycin, enoxacin, ciprofloxacin, pefloxacin, norfloxacin, ofloxacin, fluoroquinolone T-3262, pipemidic acid, cimetidine, etintidine, propranolol, verapamil, diltiazem, nifedipine, furosemide (frusemide), at least some anovulent agents, viloxazine, allopurinol, ticlopidine, idrocilamide, thiabendazole, disulfiram, influenza- and BCG-vaccination, interferon, and caffeine (half-life increase). In contrast, theophylline clearance (clearance/bioavailability) was found to be increased by isoprenaline (isoproterenol), terbutaline, some corticosteroids, phenytoin, phenobarbital, activated charcoal, felodipine moricizine, benzodiazepines and sulfinpyrazone - typically by about 25%, but sometimes by as much as 80% or more. For several of these concomitant medications, however, only some of the published studies can substantiate an influence, which may highlight the sensitivity of some interactions to particular experimental and/or clinical conditions, e.g. with terbutaline, erythromycin, ciprofloxacin, norfloxacin, ofloxacin, phenobarbital, cimetidine, verapamil, diltiazem, nifedipine, anovulents, allopurinol and influenza vaccination. Moreover, reports both of inhibition and of induction of theophylline clearance by each of rifampicin and isoniazid have appeared. Nevertheless, under investigation many medications have not been found to perceptibly influence theophylline disposition kinetics, e.g. ephedrine, orciprenaline (metaproterenol), prednisone, prednisolone, temelastine, terfenadine, mequitazine, picumast, repirinast, josamycin, midecamycin, miocamycin, spiramycin, amoxicillin, ampicillin, cefalexin, cefaclor, ceftibuten, cotrimoxazole (trimethoprim plus sulfamethoxazole), tetracycline, doxycycline, lomefloxacin, fluoroquinolones NY-198 and AM-833, nalidixic acid, lincomycin, metronidazole, certain antacids, ranitidine, roxatidine, pirenzepine, rioprostil, metoclopramide, metoprolol, atenolol, nadolol, medroxyprogesterone, dextropropoxyphene (propoxyphene), piroxicam, ozagrel, mebendazole and ascorbic acid.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Pharmacokinetic interactions between theophylline and other medication (Part I). 167 42

Primary steps in the metabolism of caffeine and theophylline are cleavage of methyl groups and/or hydroxylation at position 8, mediated by cytochromes P450. V79 Chinese hamster cells genetically engineered for stable expression of single forms of rat cytochromes P450IA1, P450IA2 and P450IIBI and human P450IA2 and rat liver epithelial cells expressing murine P450IA2 were used to overcome problems arising in the proper allocation of metabolic pathways to specific isoforms by conventional techniques. These cell lines were exposed to caffeine and/or theophylline, and concentrations of metabolites formed in the medium were determined by HPLC. Caffeine was metabolized by human, rat and murine P450IA2, resulting in the formation of four primary demethylated and hydroxylated metabolites. However, there were differences in the relative amounts of the metabolites. The human and the mouse P450IA2 isoforms predominantly mediated 3-demethylation of caffeine. The rat cytochrome P450IA2 mediated both 3-demethylation and 1-demethylation of caffeine to a similar extent. Theophylline was metabolized mainly via 8-hydroxylation. All cell lines tested were able to carry out this reaction, with highest activities in cell lines expressing rat or human P450IA2, or rat P450IA1. These results support the hypothesis that caffeine plasma clearance is a specific in vivo probe for determining human P450IA2 activity.
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PMID:Biotransformation of caffeine and theophylline in mammalian cell lines genetically engineered for expression of single cytochrome P450 isoforms. 173 11

An animal model suitable for in vivo studies of interferon-mediated suppression of hepatic oxidative drug metabolism has been developed. Rats were injected with either recombinant human interferon alpha A, recombinant human interferon gamma, recombinant rat interferon gamma, or vehicle and experiments were performed 24 h later. In some animals theophylline elimination was determined twice (10 days apart), once after interferon and once after vehicle. Theophylline clearance was also determined in the isolated perfused rat liver after pretreatment of animals with interferon or vehicle. Pretreatment of animals with rat interferon gamma significantly reduced theophylline clearance in the intact rat but neither human interferon alpha A nor human interferon gamma altered theophylline elimination in vivo. Similar results were observed in the isolated perfused rat liver. We then examined whether the effects of interferon on hepatic drug metabolism were generalized or confined to individual cytochrome P450 isozymes; androstenedione hydroxylation pathways were used as catalytic probes for individual cytochrome P450 isozymes. Rat interferon gamma (but not human interferon alpha A) decreased levels of total hepatic microsomal P450 and reduced androstenedione 16 beta-hydroxylation. The formation of three other hydroxylated androstenedione metabolites appeared reduced to a similar extent, although these changes were not significant. It is concluded that autologous but not heterologous interferons impair oxidative drug metabolism in the rat. The reduction of hepatic P450 produced by interferon may result from the suppression of multiple isozymes.
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PMID:Rat but not human interferons suppress hepatic oxidative drug metabolism in rats. 247 60

Polycyclic aromatic hydrocarbons present in cigarette smoke induce cytochromes P4501A1 and P4501A2. These isozymes are of toxicological importance because they convert several environmental pollutants to reactive intermediates that form covalent adducts with cellular DNA resulting in mutations and/or malignant transformations. The aim of our research was to investigate whether theophylline metabolites could be used as probes for P4501A1 and P4501A2. It is known that at least two human P450 isozymes are involved in theophylline metabolism. The N-demethylations of theophylline to 3-methylxanthine (3-MX) and 1-methylxanthine (1-MX) appear to be mediated by P4501A1 and/or P4501A2 and the 8-hydroxylation by different isozymes. Theophylline metabolism was measured in liver microsomes from control, benzo(a)pyrene (BP)-, and isosafrole (ISO)-induced rats. Theophylline was also incubated in microsomes prepared from cells expressing high levels of human P4501A1 and P4501A2. A plot of v vs. v/S was linear for 3-MX in the ISO-induced microsomes, but nonlinear for 1-MX, indicating that P4501A2 mainly forms 3-MX, whereas P4501A1 and 1A2 probably mediate 1-MX. A similar nonlinear relation was also obtained in the BP-induced microsomes. Incubation of theophylline in the microsomes from the cells indicated that only 1-MX could be measured in cells expressing P4501A1, and both 1-MX and 3-MX were formed in the P4501A2 cell microsomes. Therefore 1-MX seems to be mediated by P4501A1/P4501A2 and 3-MX specifically by P4501A2, and theophylline N-demethylations can be used as probes for P4501A1 and P4501A2.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Theophylline N-demethylations as probes for P4501A1 and P4501A2. 789 98

We examined the inhibitory behavior of theophylline oxidations and a variety of cytochrome P450 (P450)-dependent metabolism in the presence of mexiletine (MEX), using hepatic microsomes from both control mice and mice exposed to beta-naphthoflavone (beta-NF). Theophylline metabolism, which is mainly catalyzed by CYP1A2, was susceptible to competitive inhibition by MEX. The calculated inhibition constants (Ki) for theophylline 3-demethylation and its 8-hydroxylation were 4.3 microM and 8.3 microM, respectively, which are comparable to the recommended therapeutic serum range for MEX. The inhibitory potency of MEX on cytochrome P450-dependent enzyme activities diverged among the several metabolic reactions, which were probes for CYP1A, 2A, 2C, 2D, 2E and 3A subfamilies. The Ki value (6.7 microM) for methoxyresorufin O-demethylation mediated by CYP1A2 agreed with those from theophylline oxidations. These metabolic reactions exhibited the smallest Ki values, 1-3 orders of magnitude lower than activities of other constitutive cytochrome P450 species. Similar degrees of inhibition were observed in CYP1A1, a beta-NF-inducible isoform with a relatively high conformity to CYP1A2. These results indicate that MEX acts as a selective and potent inhibitor of the CYP1A enzymes responsible for oxidative biotransformation of chemicals such as theophylline. This evidence provides a fundamental explanation for the pharmacokinetic interactions experienced in clinical practice.
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PMID:Preferential inhibition of CYP1A enzymes in hepatic microsomes by mexiletine. 1051 Jul 42