Effect of fluvoxamine therapy on the activities of CYP1A2, CYP2D6, and CYP3A as determined by phenotyping*

Kashuba, Angela D. M.; Nafziger, Anne N.; Kearns, Gregory L.; Leeder, J. Steven; Gotschall, Russell; Rocci, Mario L.; Kulawy, Robert; Beck, Debra J.; Bertino, Joseph S.

doi:10.1016/s0009-9236(98)90174-6

Cited by 63 publications

(62 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These suggested that there is a large inter-individual difference in bioavailability of fluvoxamine. Many previous papers described the effect of fluvoxamine on the pharmacokinetics of other drugs, which were metabolized by CYP2C19, 8 CYP3A4, [26][27][28] and CYP1A2. 28,29 However, the specific isoenzymes involved in fluvoxamine metabolism have not been identified; nevertheless, in vitro and in vivo the drug potently inhibits the metabolism of substrates for CYP1A2.…”

Section: Discussionmentioning

confidence: 99%

“…Many previous papers described the effect of fluvoxamine on the pharmacokinetics of other drugs, which were metabolized by CYP2C19, 8 CYP3A4, [26][27][28] and CYP1A2. 28,29 However, the specific isoenzymes involved in fluvoxamine metabolism have not been identified; nevertheless, in vitro and in vivo the drug potently inhibits the metabolism of substrates for CYP1A2. 29 We consider that our present HPLC method for the determination of fluvoxamine and fluvoxamino acid can be confidently applied to study in fluvoxamine for in vivo and in vitro drug metabolism.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

High-Performance Liquid Chromatographic Determination of Fluvoxamine and Fluvoxamino Acid in Human Plasma

et al. 2003

View full text Add to dashboard Cite

IntroductionFluvoxamine, 5-methyl-4′-trifluoromethylvalerophenone(E)-O-2-aminoethyloxime monomaleate, is one of several antidepressant agents known as selective serotonin reuptake inhibitors (SSRIS). The efficacy of fluvoxamine in depression has been reviewed in previous papers. 1,2 The clinical pharmacokinetics of fluvoxamine were also described in a previous paper. 3 Negligible amounts of fluvoxamine are excreted unchanged in the human urine. Urinary fluvoxamine metabolites have been identified as consisting of at least 9 different compounds. About 65% of these metabolites resulted from oxidative demethylation of the aliphatic methoxyl group, and 15% of metabolites are formed by degradation at the primary amino group. Fluvoxamino acid is the main primary metabolite in humans. 4 Therefore, the monitoring of fluvoxamino acid on the drug interaction study of fluvoxamine will be able to detect slight changes of fluvoxamine metabolism by co-administered drug in healthy volunteers and/or patients.The pharmacokinetics of fluvoxamino acid in human has not yet been studied sufficiently.Methods for the fluvoxamine by GC-MS, 12 HPLC with liquidliquid extraction of plasma samples [13][14][15][16][17] and HPLC with solidphase in-line extraction 18,19 were described in previous papers. The liquid-liquid extraction methods are not completely satisfactory because they are time-consuming and require a tedious procedure. We have reported a simple extraction method of several drugs and their metabolites by using a solid phase extraction cartridge. [20][21][22][23] However, an off-line solid phase extraction method for fluvoxamine has not been reported in previous papers. There is also no report for simultaneous determination of fluvoxamine and fluvoxamino acid in human plasma by HPLC.The extraction of fluvoxamine and fluvoxamino acid in human plasma using a solid phase method has some problems: one is the simultaneous extraction from a complex mixture of both acidic and basic compounds. Therefore, a specific extraction method and an efficient chromatographic system without interfering peaks was needed A high-performance liquid chromatographic (HPLC) method has been developed for the simultaneous determination of fluvoxamine and its major metabolite fluvoxamino acid in plasma. Fluvoxamine and fluvoxamino acid in plasma were extracted using a C18 bonded-solid phase cartridge, followed by C4 reversed-phase HPLC separation. Fluvoxamine, fluvoxamino acid and moperone as an internal standard were detected by ultraviolet absorbance at 254 nm. It was possible to determine both fluvoxamine and fluvoxamino acid in the concentration range of 25.0 -200.0 ng/mL, respectively. The detection limits of both fluvoxamine and fluvoxamino acid were 10.0 ng/mL, respectively. The mean recoveries of fluvoxamine and fluvoxamino acid added to plasma were more than 94.0% and 96.5%, with a coefficient of variation of less than 7.6% and 8.2%, respectively. This method has been used for the simultaneous determination of steady-state plasma concentration (C...

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

High-Performance Liquid Chromatographic Determination of Fluvoxamine and Fluvoxamino Acid in Human Plasma

et al. 2003

View full text Add to dashboard Cite

show abstract

“…CYP1A2 activity was defined by the ratio (1-methylurate + 1-methylxanthine + 5-acetylamino-6-formylamino-3-methyluracil)/1,7-dimethylurate, FMO3 activity by 3,7-dimethylxanthine/caffeine, NAT-2 activity by 5-acetylamino-6-formylamino-3-methyluracil/(1-methylxanthine + 1-methylurate + 5-acetylamino-6-formylamino-3-methyluracil), and xanthine oxidase activity by 1-methylurate/ (1-methylxanthine + 1-methylurate). Samples for dextromethorphan metabolism were processed and analyzed by HPLC using the procedure of Kashuba et al (27). CYP2D6 activity was defined by the ratio of parent drug dextromethorphan to its metabolite dextrorphan.…”

Section: Methodsmentioning

confidence: 99%

A Phase I Study of Indole-3-Carbinol in Women: Tolerability and Effects

Reed

Peterson

Smith

et al. 2005

Cancer Epidemiology, Biomarkers &Amp; Prevention

141

View full text Add to dashboard Cite

We completed a phase I trial of indole-3-carbinol (I3C) in 17 women (1 postmenopausal and 16 premenopausal) from a high-risk breast cancer cohort. After a 4-week placebo runin period, subjects ingested 400 mg I3C daily for 4 weeks followed by a 4-week period of 800 mg I3C daily. These chronic doses were tolerated well by all subjects. Hormonal variables were measured near the end of the placebo and dosing periods, including determination of the urinary 2-hydroxyestrone/16A-hydroxyestrone ratio. Measurements were made during the follicular phase for premenopausal women. Serum estradiol, progesterone, luteinizing hormone, follicle-stimulating hormone, and sex hormone binding globulin showed no significant changes in response to I3C. Caffeine was used to probe for cytochrome P450 1A2 (CYP1A2), N-acetyltransferase-2 (NAT-2), and xanthine oxidase. Comparing the results from the placebo and the 800 mg daily dose period, CYP1A2 was elevated by I3C in 94% of the subjects, with a mean increase of 4.1-fold. In subjects with high NAT-2 activities, these were decreased to 11% by I3C administration but not altered if NAT-2 activity was initially low. Xanthine oxidase was not affected. Lymphocyte glutathione S-transferase activity was increased by 69% in response to I3C. The apparent induction of CYP1A2 was mirrored by a 66% increase in the urinary 2-hydroxyestrone/16A-hydroxyestrone ratio in response to I3C. The maximal increase was observed with the 400 mg daily dose of I3C, with no further increase found at 800 mg daily. If the ratio of hydroxylated estrone metabolites is a biomarker for chemoprevention, as suggested, then 400 mg I3C daily will elicit a maximal protective effect. (Cancer Epidemiol Biomarkers Prev 2005;14(8):1953 -60)

show abstract

“…In addition, fluvoxamine, a potent inhibitor of CYP1A2, [46][47][48][49] increases the plasma concentration of typical antipsychotics (eg haloperidol), 50 further suggesting the involvement of CYP1A2 in antipsychotic metabolism. It should be noted that fluvoxamine can also inhibit other CYP enzymes (eg CYP2D6); 47 however, the in vitro inhibitory potency of fluvoxamine for CYP1A2 (K i = 0.24 M) 51 is approximately one order of magnitude greater than CYP2D6 (K i = 16.6 M) 52 and CYP3A4 (K i = 10.2 M). 52 Taken together, and considering the strong epidemiological association between smoking and schizophrenia, CYP1A2 can be viewed as another CYP (in addition to CYP2D6) which may contribute to disposition of typical antipsychotics in patients with schizophrenia during long-term treatment.…”

Section: Molecular Psychiatrymentioning

confidence: 99%

A functional polymorphism of the cytochrome P450 1A2 (CYP1A2) gene: association with tardive dyskinesia in schizophrenia

et al. 2000

View full text Add to dashboard Cite

Effect of fluvoxamine therapy on the activities of CYP1A2, CYP2D6, and CYP3A as determined by phenotyping*

Abstract: We concluded that fluvoxamine may cause significant inhibition of CYP1A2, CYP2D6, and CYP3A activity. This metabolic inhibition may have serious implications for a variety medications.

Cited by 63 publications

References 31 publications

High-Performance Liquid Chromatographic Determination of Fluvoxamine and Fluvoxamino Acid in Human Plasma

High-Performance Liquid Chromatographic Determination of Fluvoxamine and Fluvoxamino Acid in Human Plasma

A Phase I Study of Indole-3-Carbinol in Women: Tolerability and Effects

A functional polymorphism of the cytochrome P450 1A2 (CYP1A2) gene: association with tardive dyskinesia in schizophrenia

Contact Info

Product

Resources

About