Effect of fluvoxamine therapy on the activities of CYP1A2, CYP2D6, and CYP3A as determined by phenotyping.
OBJECTIVE
To determine the effect of 150 mg/day fluvoxamine on the activities of CYP1A2, CYP2D6, CYP3A, N-acetyltransferase-2 (NAT2), and xanthine oxidase (XO) by phenotyping with caffeine, dextromethorphan, and midazolam.


METHODS
Oral caffeine (2 mg/kg), oral dextromethorphan (30 mg), and intravenous midazolam (0.025 mg/kg) were administered to 10 white male volunteers every 14 days for 4 months and to 10 white premenopausal female volunteers during the midfollicular and midluteal phases of the menstrual cycle for 4 complete cycles (8 total phenotyping measures). The first 6 phenotyping measures were used to establish baseline activity. Subjects were given 150 mg/day fluvoxamine for the fourth month or cycle of the study. Enzyme activity for CYP1A2, CYP2D6, NAT2, and XO was expressed as urinary metabolite ratios. Midazolam plasma clearance was used to express CYP3A activity.


RESULTS
No difference between baseline and weeks 2 and 4 of fluvoxamine therapy was observed for NAT2 or XO metabolite ratios. For CYP1A2, CYP2D6, and CYP3A phenotypes, significant differences existed between baseline and fluvoxamine therapy. For CYP1A2, the mean urinary metabolite ratio (+/-SD) was 7.53 +/- 7.44 at baseline and 4.30 +/- 2.82 with fluvoxamine ( P = .012). Mean CYP2D6 molar urinary dextromethorphan ratios before and after fluvoxamine therapy were 0.00780 +/- 0.00694 and 0.0153 +/- 0.0127, respectively (P = .011). Midazolam clearance decreased from 0.0081 +/ 0.0024 L/min/kg at baseline to 0.0054 +/- 0.0021 L/min/kg with therapy (P = .0091). For CYP1A2, CYP2D6, and CYP3A, fluvoxamine therapy changed the phenotyping measures by a median of -44.4%, 123.5%, and -34.4%, respectively.


CONCLUSIONS
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.
Kashuba
A D
AD
Department of Medicine, Bassett Healthcare, Cooperstown, NY 13326, USA.
Nafziger
A N
AN
Kearns
G L
GL
Leeder
J S
JS
Gotschall
R
R
Rocci
M L
ML
Kulawy
R W
RW
Beck
D J
DJ
Bertino
J S
JS
D000123:Acetyltransferases / Q000187:drug effects*; D000328:Adult; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D000996:Antitussive Agents / Q000378:metabolism; D001189:Aryl Hydrocarbon Hydroxylases; D002110:Caffeine / Q000378:metabolism; D000697:Central Nervous System Stimulants / Q000378:metabolism; D065609:Cytochrome P-450 CYP1A2 Inhibitors; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003915:Dextromethorphan / Q000378:metabolism; D005260:Female; D016666:Fluvoxamine / Q000494:pharmacology*; D005838:Genotype; D006801:Humans; D006993:Hypnotics and Sedatives / Q000378:metabolism; D008297:Male; D008874:Midazolam / Q000378:metabolism; D010089:Oxidoreductases, N-Demethylating / Q000037:antagonists & inhibitors; D010641:Phenotype; D012016:Reference Values; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D013997:Time Factors; D014969:Xanthine Oxidase / Q000187:drug effects*
D000123:Acetyltransferases; D014151:Anti-Anxiety Agents; D000996:Antitussive Agents; D001189:Aryl Hydrocarbon Hydroxylases; D002110:Caffeine; D000697:Central Nervous System Stimulants; D065609:Cytochrome P-450 CYP1A2 Inhibitors; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003915:Dextromethorphan; D016666:Fluvoxamine; D006993:Hypnotics and Sedatives; D008874:Midazolam; D010089:Oxidoreductases, N-Demethylating; D017367:Selective Serotonin Reuptake Inhibitors; D014969:Xanthine Oxidase