Re: metabolism of Singulair - and about onion rinse

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This is a long post about the liver, Singulair, Quercetin, onions and drug interactions.Singulair and the liverSingulair (Montelukast) is metabolized in the liver and seems to have a known (though not automatic?) hepatotoxic effect. One lady even died while on Singulair by overcharging her liver with herbal supplements to lose weight, but do note that these supplements were hepatotoxic by themselves, so sorting out the part of Singulair from the part of the supplements is not obvious. It does however mean that since Singulair taxes the liver, it would be wise not add too many extra loads, especially herbs of unknown liver effect (see Abstract 1 below).There is another report of rare liver toxicity with Montelukast, but the full abstract is not available (see below). An available article does say that Montelukast may raise liver function (meaning : overload the liver) in a percentage of patients (see Abstract 3).This is probably because Montelukast inhibits a liver enzyme called "Cytochrome P450 - CYP 2C8". There are several cytochrome P450 enzymes ; some drugs don't need them to clear, and there are drugs that need them to clear, using one type of Cytochrome enzyme, while other drugs may clear using another Cytochrome type. So, if Montelukast uses and blocks enzyme 2C8, anything else that needs enzyme 2C8 to clear out is partially or totally blocked, depending on the respective affinities of the molecules for the cytochrome enzyme in question, and the blood concentrations of that "anything else" and Montelukast would both rise longer and higher than if only of these compounds were present alone (see Abstract 2 below).For instance, the article (Abstract 2, free article) says that Quercetin, a flavonoid, also uses CYP 2C8 ; so, theoretically, taking Quercetin orally while on Montelukast might well result in a drug-food interaction at the level of the cytochrome enzyme, with both Montelukast and Quercetin blood levels staying higher longer than normal. Whether this would be really dangerous or not for the liver is another issue.Overall, the liver interaction potential of Singulair is serious, because Montelukast has been determined to be the most potent CYP 2C8 inhibitor studied (see Abstract 4 below).So, do watch out when taking oral drugs that also use CYP 2C8 to clear. These would normally be mentioned in the Singulair notice under the "interactions" title, but Abstract 4 gives a good list (see below), and I suspect that many of us take orally at least one of these drugs from time to time.I underline "orally", because nose sprays usually have strictly no liver effect, but do note that some inhaled drugs may have liver effects, because some molecules are partially absorbed into the bloodstream via the lungs. This depends totally on the molecule, its concentration, etc.Quercetin and onion rinseWhile we are speaking about Quercetin, have a look at :http://en.wikipedia.org/wiki/QuercetinI am always amazed at the richness of information in Wikipedia articles, and the one on Quercetin is no exception. We learn some very interesting facts, for instance :- onion is one of the foods rich in Quercetin (see Wiki extract below), especially the outermost rings,- Quercetin is an anti-inflammatory, and especially an anti-histaminic, which is interesting if confirmed because histamine is one of the substances released in allergic reactions,- Quercetin is a mast cell inhibitor ; now, if confirmed (I will try to have a look), this would be very interesting because mast cells are one of the major mediators of Samter's.So, would onion rinse work because onions contain Quercetin, an anti-histaminic and mast-cell inhibitor? The conclusion is very tempting, but needs a bit more research, at least because onions contain many more compounds than Quercetin alone. But the link seems worth exploring.Quercetin and antibioticsAlso have a look at this in the Wiki page on Quercetin :"Drug interactionsQuercetin is contraindicated with antibiotics; it may interact with fluoroquinolones (a type of medicinal antibiotic), as quercetin competitively binds to bacterial DNA gyrase. Whether this inhibits or enhances the effect of fluoroquinolones is not entirely clear.[10] Quercetin is also a potent inhibitor of CYP3A4, an enzyme that breaks down most drugs in the body.[11] As such, quercetin would be expected to increase serum levels, and therefore effects, of drugs metabolized by this enzyme."This is a good example of drug-food interaction, but this time via a mecanism different from the Cytochrome way. So, if on quinolone antibiotics to cure a bout of chronic sinusitis, avoid Quercetin-rich foods because otherwise the antibiotic would clear out poorly, and quinolones are known to have potentially serious side effects.----------------Abstract 1----------------Digestive and Liver DiseaseVolume 39, Issue 10, October 2007, Pages 953-955Copyright © 2006 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd.Brief Clinical ObservationFatal liver failure following food supplements during chronic treatment with montelukastG.C. Actis, E. Bugianesi, A. Ottobrelli and M. RizzettoDivision of Gastroenterology, Ospedale San Giovanni Battista, Torino 10126, ItalyAbstractHigh aminotransferases and prolonged prothrombin time on entering our liver unit were revealing parenchymal collapse for this 45-year-old obese woman; treatment failure led her to death. Autoimmunity, paracetamol use, alcoholism, and 's disease were all excluded as causes. Because of chronic asthma, she had been receiving a leukotriene receptor antagonist (montelukast) for 5 years before the current presentation; 1 week before onset she had had 1 week of treatment with two dietary supplements for weight control; one of these included Garcinia Cambogia, a possible cause of two recent cases of hepatitis in the USA; in addition, both formulas contained a citrus derivative that interferes cytochrome functions. We speculate on a causal relationship between the assumption of the additives and the fatal hepatitis and envisage a synergy between the additives and montelukast, which per se has well been studied as a hepatotoxic drug. Despite the speculative nature of this presentation, we believe the warning may serve to focus attention on the uncontrolled escalation of food additives going on in these days.-------------Abstract 2------------- Drug Metab Dispos. 2005 Mar;33(3):413-8. Epub 2004 Dec 17. LinksSelective inhibition of human cytochrome P4502C8 by montelukast.Walsky RL, Obach RS, Gaman EA, Gleeson JP, Proctor WR.Department of Pharmacokinetics, Dynamics, and Drug Metabolism, Pfizer Global Research and Development, Groton Laboratories, Groton, CT 06340, USA.The leukotriene receptor antagonist montelukast was examined for its inhibition of the human drug-metabolizing enzyme cytochrome P4502C8 (CYP2C8). Montelukast was demonstrated to be a potent inhibitor of CYP2C8-catalyzed amodiaquine N-deethylase, rosiglitazone N-demethylase, and paclitaxel 6alpha-hydroxylase in human liver microsomes. Inhibition was also observed when the reaction was catalyzed by recombinant heterologously expressed CYP2C8. The mechanism of inhibition was competitive, with K(i) values ranging from 0.0092 to 0.15 microM. Inhibition potency was highly dependent on the microsomal protein concentration. Increasing the microsomal protein concentration by 80-fold yielded a 100-fold decrease in inhibition potency. Preincubation of montelukast with human liver microsomes and NADPH did not alter the inhibition potency, suggesting that montelukast is not a mechanism-based inactivator. Montelukast was a selective inhibitor for human CYP2C8; inhibition of other human cytochrome P450 enzymes was substantially less. These in vitro data support the use of montelukast as a selective CYP2C8 inhibitor that could be used to determine the contribution of this enzyme to drug metabolism reactions. These data also raise the possibility that montelukast could have an effect on the metabolic clearance of drugs possessing CYP2C8-catalyzed metabolism as a major clearance pathway, thereby eliciting pharmacokinetic drug-drug interactions.------------------Other abstract------------------Ann Saudi Med. 2007 Nov-Dec;27(6):462-3.LinksProbable montelukast-induced hepatotoxicity in a pediatric patient: case report.Incecik F, Onlen Y, Sangun O, Akoglu S.----------------Abstract 3----------------Indian Pediatr. 2006 Sep;43(9):780-5. LinksEfficacy and safety of montelukast as monotherapy in children with mild persistent asthma.Ghosh G, Manglik AK, Roy S.Shree Jain Hospital and Research Center, Howrah, West Bengal, India. ghoshped@...OBJECTIVE: To study the efficacy and tolerability of montelukast as monotherapy in the treatment of mild persistent bronchial asthma. DESIGN: Open, non-comparative, prospective, 12-month study. SETTING: Asthma clinic in urban multi-speciality trust hospital. METHODS: Children (age 3-11 yrs) with mild persistent asthma, not on any prophylactic drugs were enrolled consecutively (from January to December 2003) and started on 4 mg (2-4 yrs) or 5mg (<4 yrs) montelukast for a period of 12 weeks. Efficacy was assessed by improvements in clinical score, peak expiratory flow rates (PEFR), spirometry measurements and reduction in reliever drug requirement after 4 and 12 weeks of therapy. Side effects were also judged after 12 weeks of therapy. RESULTS: 50 children (mean age 5.41 +/-2.11 years) completed the study. There was association with positive family history (92%), allergic rhinitis (64%), exercise induced asthma (40%), cough variant asthma (24%), seasonal asthma (80%) and high IgE (12%) levels. Clinical scores, viz, activity, wheeze and cough, improved effectively from (1.64 +/-0.5253) at baseline to (0.7 +/-0.7071) and (1.72 +/-0.701) to (0.92 +/-0.6952) and (1.5 +/-0.6145) to (0.88 +/-0.8241) respectively after 12 weeks of therapy. Significant clinical improvement (p >0.001) was also noted after 4 weeks of therapy. Peak expiratory flow rates (done in 19 cases) documented improvement from (120.21 +/-12.23) at baseline to (135.41 +/-23.34) after 12 weeks. FEV1 / FVC (done in 11 cases) improved from (71.44 +/-1.35%) to (87.10 +/-8.34%) after 12 weeks. Mean improvement in all the parameters demonstrated P value less than >.001. A total of 19 of 50 cases showed mild side-effects as anorexia (16%), elevated liver function tests (18%) and headache (10%). CONCLUSION: The clinical outcome showed significant improvement (p < 0.01) after 4 and 12 weeks.--------------------Abstract 4--------------------J Clin Pharmacol. 2005 Jan;45(1):68-78. LinksExamination of 209 drugs for inhibition of cytochrome P450 2C8.Walsky RL, Gaman EA, Obach RS.Pharmacokientics, Pharmacodynamics,, and Drug Metabolism, Pfizer Global Research and Development, Groton/New London Laboratories, Groton, CT 06340, USA.Cytochrome P450 2C8 is involved in the metabolism of drugs such as paclitaxel, repaglinide, rosiglitazone, and cerivastatin, among others. An in vitro assessment of 209 frequently prescribed drugs and related xenobiotics was carried out to examine their potential to inhibit CYP2C8. A validated sensitive, moderate-throughput high-performance liquid chromatography/tandem mass spectrometry (HPLC/MS/MS) assay was used to detect N-desethylamodiaquine, the CYP2C8-derived major metabolite of amodiaquine metabolism, using heterologously expressed recombinant CYP2C8 (rhCYP2C8) and pooled human liver microsomes. The 209 drugs were first tested at 30 muM for their ability to inhibit rhCYP2C8. Forty-eight compounds exhibited greater than 50% inhibition and were further evaluated for measurement of IC50. The six most potent inhibitors (IC50 <1 microM) from this set were measured for IC50 in pooled human liver microsomes, and the most potent inhibitor identified was the leukotriene receptor antagonist, montelukast (IC50 = 19.6 nM). Inhibitors of CYP2C8 were identified from a wide variety of therapeutic classes, with no single class predominating.Other potent inhibitors included candesartan cilexetil (cyclohexylcarbonate ester prodrug of candesartan), zafirlukast, clotrimazole, felodipine, and mometasone furoate.Seventeen moderate inhibitors of rhCYP2C8 (1 < IC50 < 10 microM) included salmeterol, raloxifene, fenofibrate, ritonavir, levothyroxine, tamoxifen, loratadine, quercetin, oxybutynin, medroxyprogesterone, simvastatin, ketoconazole, ethinyl estradiol, spironolactone, lovastatin, nifedipine, and irbesartan. These in vitro data were used along with clinical pharmacokinetic information in predicting potential drug-drug interactions that could occur by inhibition of CYP2C8. Although almost all drugs tested are not expected to cause drug interactions via inhibition of CYP2C8, montelukast was identified as being of concern as a potential inhibitor of clinical relevance. These findings are discussed in context to potential drug interactions that could be observed between these agents and drugs for which CYP2C8 is involved in metabolism and warrant investigation of the possibility of clinical drug interactions mediated by inhibition of this enzyme.-------------------------From Wiki : Quercetin-------------------------Foods rich in quercetin include capers (1800mg/kg)[4], lovage(1700mg/kg), apples (440mg/kg), tea (Camellia sinensis), onions (higherconcentrations of quercetin occur in the outermost rings[5]), redgrapes, citrus fruits, broccoli and other leafy green vegetables,cherries, and a number of berries including raspberry, bog whortleberry(158 mg/kg, fresh weight), lingonberry (cultivated 74mg/kg, wild 146mg/kg), cranberry (cultivated 83 mg/kg, wild 121 mg/kg), chokeberry (89mg/kg), sweet rowan (85 mg/kg), rowanberry (63 mg/kg), sea buckthornberry (62 mg/kg), crowberry (cultivated 53mg/kg, wild 56 mg/kg),[6] andthe fruit of the prickly pear cactus. A recent study found thatorganically grown tomatoes had 79% more quercetin than "conventionallygrown".[7]A study[8] by the University of Queensland, Australia, has alsoindicated the presence of quercetin in varieties of honey, includinghoney derived from eucalyptus and tea tree flowers.[9](...)Quercetin is found to be the most active of the flavonoids in studies,[citation needed] and many medicinal plants owe much of their activity to their high quercetin content. Quercetin has demonstrated significant anti-inflammatory activity because of direct inhibition of several initial processes of inflammation.[1] For example, it inhibits both the manufacture and release of histamine and other allergic/inflammatory mediators. In addition, it exerts potent antioxidant activity and vitamin C-sparing action[citation needed].Quercetin also shows anti-tumour properties. A study in the British Journal of Cancer showed that, when treated with a combination of quercetin and ultrasound at 20 kHz for 1 minute duration, skin and prostate cancers show a 90% mortality within 48 hours with no visible mortality of normal cells.[2] Note that ultrasound also promotes topical absorption by up to 1,000 times making the use of topical quercetin and ultrasound wands an interesting proposition.Recent studies have supported that quercetin can help men with chronic prostatitis, and both men and women with interstitial cystitis, possibly because of its action as a mast cell inhibitor.[3]Quercetin may have positive effects in combating or helping to prevent cancer, prostatitis, heart disease, cataracts, allergies/inflammations, and respiratory diseases such as bronchitis and asthma[citation needed]. It also has antidepressant properties.[citation needed]> > >> > > I just found out something that, if it's true, may explain why > some of > > > us don't get any help from Singulair. I don't have the time to > > > research it right now, but supposedly 40 percent of people do not > > > metabolize Singulair. Therefore, it wouldn't have any effect for > them, > > > because it wouldn't be broken down into the active compound in > your > > > body.> > > > > > I don't know any more about it, but I would hope at some point > you > > > could be tested for this. That way people wouldn't wonder if > it's > > > working for them or not. I apparently do metabolize it, because > it > > > most definitely works for me.> > > > > > Lori> > >> >>