Effect of cigarette smoking on fluvoxamine pharmacokinetics in humans

Spigset, Olav; Carleborg, Lena; Hedenmalm, Karin; Dahlqvist, Rune

doi:10.1016/0009-9236(95)90052-7

Cited by 92 publications

(65 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This has been shown for haloperidol (Jann et al, 1986) and tacrine (Zevin and Benowitz, 1999). Other examples are: fluvoxamine levels in smokers are 1/3 that of nonsmokers (Spigset et al, 1995), clozapine levels are 1/3 lower for men, 1/5 for women compared with nonsmokers (Haring et al, 1989), and smoker olanzapine levels are 1/5 that of nonsmokers (Carrillo et al, 2003). Clearly cessation of smoking can cause "overdose" toxicity for a patient taking any of these medications and then stops smoking.…”

Section: Polycyclic Hydrocarbons and Drug Metabolism 11mentioning

confidence: 94%

Cigarette Smoking, Coffee Drinking, and Ingestion of Charcoal-Broiled Beef as Potential Modifiers of Drug Therapy and Confounders of Clinical Trials

Conney¹,

Reidenberg²

2012

J Pharmacol Exp Ther

View full text Add to dashboard Cite

A pathway of research is described, leading from the finding of an inhibitory effect of 3-methylcholanthrene on the carcinogenicity of an aminoazo dye, to the induction of drug-metabolizing enzymes by 3-methylcholanthrene, benzo[a]pyrene, and other polycyclic aromatic hydrocarbons, to the demonstration of enhanced drug metabolism in cigarette smokers, coffee drinkers, and people who eat charcoal-broiled beef. The results of these studies indicate that cigarette smoking, coffee drinking, and the ingestion of charcoal-broiled beef (all resulting in exposure to polycyclic aromatic hydrocarbons) can influence the dosing regimen needed for proper drug therapy and are potential confounders of clinical trials with drugs metabolized by polycyclic aromatic hydrocarbon-inducible enzymes.

show abstract

Section: Polycyclic Hydrocarbons and Drug Metabolism 11mentioning

confidence: 94%

Cigarette Smoking, Coffee Drinking, and Ingestion of Charcoal-Broiled Beef as Potential Modifiers of Drug Therapy and Confounders of Clinical Trials

Conney¹,

Reidenberg²

2012

J Pharmacol Exp Ther

View full text Add to dashboard Cite

show abstract

“…Fluvoxamine is oxidated by CYPlA2 and CYP2D6 (Spigset et al 1995;Carrillo et al 1996), and fluvoxamine is a very potent inhibitor of the former enzyme (Skjelbo & Brrasen 1992;Brrasen et al 1993;Rasmussen et al 1995). Accordingly fluvoxamine causes pharmacokinetic interactions with drugs metabolised by CYPlA2, such as theophylline (Sperber 1991;Diot et al 1991), caffeine (Jeppesen et al 1996), imipramine (Spina et al 1992), clomipramine (Bertschy et al 1991) and clozapine (Jerling et al 1994;Hiemke et al 1994).…”

mentioning

confidence: 99%

Fluvoxamine is a Potent Inhibitor of the Metabolism of Caffeine in vitro

Rasmussen

Nielsen

Brøsen

1998

Pharmacology & Toxicology

View full text Add to dashboard Cite

Abstract:The selective serotonin re-uptake inhibitor, fluvoxamine, is a very potent inhibitor of CYPlA2, and accordingly causes pharmacokinetic interactions with drugs metabolised by CYPlA2, such as caffeine, theophylline, imipramine, tacrine and clozapine. Interaction between caffeine and fluvoxamine has been described in vivo, leading to lowering of total clearance of caffeine by 80% during fluvoxamine intake. The main purpose of the present study was to evaluate this interaction in vitro in human liver microsomes. A high-performance liquid chromatography method was developed in order to assay 1,3-dimethylxanthine, 1,7-dimethylxanthine, 3,7-dimethylxanthine and 1,3,7-trimethyluric acid formed from caffeine by human liver microsomes. The limit of detection was 0.06 nmol . mg protein-' . hr-l. As expected, fluvoxamine was a very potent inhibitor of the formation of the N-demethylated caffeine metabolites, displaying Ki values of 0.08-0.28 pM. The formation of 1,7-dimethylxanthine was virtually abolished by 10 pM of fluvoxamine, indicating that the N3-demethylation of caffeine is almost exclusively catalysed by CYPlA2. The CYP3A4 inhibitors, ketoconazole and bromocriptine, inhibited 1,3,7-trimethyluric acid formation with Kis of 0.75 pM and 5 pM, respectively, thus further supporting the involvement of CYP3A4 in the 8-hydroxylation of caffeine. The study shows that fluvoxamine, as expected, is a potent inhibitor of the metabolism of caffeine in vitro.Fluvoxamine is an antidepressant that belongs to the group of selective serotonin re-uptake inhibitors. Fluvoxamine is oxidated by CYPlA2 and CYP2D6 (Spigset et al. Carrillo et al. 1996), and fluvoxamine is a very potent inhibitor of the former enzyme ( Caffeine (1,3,7-trimethylxanthine) metabolism in humans is very complex and at least 14 metabolites have been identified. The main route of elimination is N3-demethylation to paraxanthine (1,7-dimethylxanthine), and this route accounts for more than 80% of the elimination of caffeine (Lelo et al. 1986). Further, caffeine is N1-and N7-demethylated to theobromine (3,7-dimethylxanthine) and theophylline (1,3-dimethylxanthine), and 8-hydroxylated to 1,3,7-trimethyluric acid. A minor amount of caffeine is excreted unchanged in the urine. All four primary caffeine metabolites are further demethylated and/or hydroxylated in vivo, but these metabolites are usually not seen in vitro. CYPlA2 has been shown to be the major enzyme catalysing the formation of 1,7-dimethylxanthine (Butler et al. 1989;Sesardic et al. 1990;Berthou et al. 1991), and to be partially involved in the formation of 3,7-dimethylxanthine and 1,3-dimethylxanthine (Grant et al. Berthou et al. 1991;Gu et al. 1992). The remainder of the formation of 3,7-dimethylxanthine and 1,3-dimethylxanthine is believed to be catalysed by CYP2E1 (Tassaneeyakul et al. 1994). At least three P450 enzymes, CYPlA2, CYP2E1 and CYP3A4 contribute to the formation of 1,3,7-trimethyluric acid (Gu et al. 1992). The interaction between caffeine and fluvoxamine has been thoroughly investi...

show abstract

“…Similarly, it has been reported that smokers had a lower fluvoxamine concentration than non-smokers after a single oral dose (50 mg) in a study of healthy volunteers. 17) Together, these results strongly suggest that smoking has a major impact on the steady-state plasma concentration of fluvoxamine in Japanese patients being treated with the drug. It is well established that smoking increases the activity of CYP1A2.…”

Section: Discussionmentioning

confidence: 81%

“…16) Several studies have shown that the disposition of fluvoxamine is affected by cigarette smoking in human, suggesting a potential role of CYP1A2 in the metabolism of fluvoxamine in addition to CYP2D6. 9,17) However, in an in vitro examination, CYP1A2 was found to be not involved in the metabolism of fluvoxamine to fluvoxamine acid.…”

mentioning

confidence: 96%

Effects of Cigarette Smoking and Cytochrome P450 2D6 Genotype on Fluvoxamine Concentration in Plasma of Japanese Patients

Katoh

Uchida

Kawai

et al. 2010

Biological & Pharmaceutical Bulletin

View full text Add to dashboard Cite

Fluvoxamine is a selective serotonin reuptake inhibitor widely used in the treatment of depression and other psychiatric diseases.1) The drug is extensively metabolized in the liver and the major metabolite in human urine is fluvoxamine acid, produced by oxidative demethylation.2) Previous in vitro results indicated that only cytochrome P450 (CYP) 2D6 catalyses the major metabolic pathway of fluvoxamine.3) The existence of genetic polymorphisms in CYP2D6 has been recognized to influence enzymatic activity, which has effects on the plasma concentrations of substrate drugs of CYP2D6. 4,5) Several mutated allele of the CYP2D6 gene causing absent enzyme activity, e.g., CYP2D6*5 and CYP2D6*14, and decreased enzyme activity, e.g., CYP2D6*10, have been reported. [6][7][8] Furthermore, human studies have shown that polymorphisms of CYP2D6 are associated with the poor metabolism of fluvoxamine, 9,10) whereas other studies reported that the CYP2D6 genotype has no major impact on its steady-state plasma concentration. 11,12) CYP1A2 is inducible by polycyclic hydrocarbons present in cigarette smoke and it is well established that cigarette smoking induces the metabolism of drugs catalyzed by CYP1A2, such as theophylline, 13,14) caffeine, 15) and imipramine.16) Several studies have shown that the disposition of fluvoxamine is affected by cigarette smoking in human, suggesting a potential role of CYP1A2 in the metabolism of fluvoxamine in addition to CYP2D6.9,17) However, in an in vitro examination, CYP1A2 was found to be not involved in the metabolism of fluvoxamine to fluvoxamine acid.3) Together, the role of CYP1A2 on the metabolism of flivoxamine is still unclear in human. In addition, a single nucleotide polymorphism in the 5Ј-flanking region of the human CYP1A2 gene, CYP1A2*1C (Ϫ3860GϾA), was reported to be associated with decreased enzyme inducibility in Japanese smokers.18) Thus, the polymorphism of CYP1A2 in relation to cigarette smoking may have an effect on the metabolism of fluvoxamine.The aim of this study was to assess the clinical impact of cigarette smoking on plasma fluvoxamine concentration in Japanese patients, and evaluate whether the CYP1A2 and CYP2D6 genotypes have effects on that concentration. MATERIALS AND METHODS DrugsPatients were treated with fluvoxamine maleate (Depromel ® , Meiji Seika Kaisha Ltd., Tokyo, Japan). DNA Extractor WB Kit was purchased from Wako Pure Chemical Industries (Osaka, Japan). All other drugs and materials were obtained from commercial source.Subjects Thirty-two Japanese patients (15 males, 17 females) receiving fluvoxamine were enrolled in this study. They were being treated at the outpatient clinic of Hamamatsu University School of Medicine Hospital, and each had normal liver and renal functions. Their ages ranged from 20 to 67 years (meanϮS.D., 39.0Ϯ15.0 years) and body weights ranged from 32.5 to 87.2 kg (56.8Ϯ12.6 kg). Six were smokers (Ն10 cigarettes/d). Fluvoxamine is a selective serotonin reuptake inhibitor widely used in the treatment of depression and other psychiat...

show abstract

Effect of cigarette smoking on fluvoxamine pharmacokinetics in humans

Abstract: Smokers had lower serum concentrations of fluvoxamine than nonsmokers after a single oral dose of fluvoxamine. This finding is consistent with a possible role of CYP1A2 in fluvoxamine metabolism.

Cited by 92 publications

References 20 publications

Cigarette Smoking, Coffee Drinking, and Ingestion of Charcoal-Broiled Beef as Potential Modifiers of Drug Therapy and Confounders of Clinical Trials

Cigarette Smoking, Coffee Drinking, and Ingestion of Charcoal-Broiled Beef as Potential Modifiers of Drug Therapy and Confounders of Clinical Trials

Fluvoxamine is a Potent Inhibitor of the Metabolism of Caffeine in vitro

Effects of Cigarette Smoking and Cytochrome P450 2D6 Genotype on Fluvoxamine Concentration in Plasma of Japanese Patients

Contact Info

Product

Resources

About