The results are consistent with a possible minor to moderate role of CYP2D6, but not CYP2C19, in fluvoxamine metabolism.

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Objective: Previous studies have shown that uvoxamine is metabolized by CYP1A2 and CYP2D6, but there is no information on the impact the various CYP enzymes have on the dierent metabolic pathways of¯uvoxamine biotransformation. The present study was designed to investigate this issue. Methods: The major¯uvoxamine metabolite, the 5-demethoxylated carboxylic acid metabolite, was analyzed in urine from 50 healthy volunteers after intake of a single oral dose of 50 mg¯uvoxamine, and the formation clearance for the metabolite (CL m ) was calculated. Of the subjects, 28 were non-smoking CYP2D6 and CYP2C19 extensive metabolizers (EMs), 12 were smokers and were thus considered to have an induced CYP1A2 activity, 5 were CYP2D6 poor metabolizers (PMs), and 5 were CYP2C19 PMs. In 11 of the nonsmoking EMs, 200 mg caeine was given at another occasion in order to calculate oral caeine clearance as a measure of CYP1A2 activity. In addition, CL m was calculated in ten other subjects given increasing doses of uvoxamine for 4 weeks. Results: Oral clearance of¯uvoxamine was signi®cantly higher in smokers, and signi®cantly lower in CYP2D6 PMs than in non-smoking EMs. CL m was 78% lower in CYP2D6 PMs than in the EMs. Smoking and being a CYP2C19 PM did not in¯uence CL m . There was no signi®cant correlation between oral caeine clearance and CL m . CL m decreased with increasing¯uvoxamine dosage, but the decrease in oral clearance was even higher. Conclusion:These results indicate that CYP2D6 catalyzes the major metabolic pathway of¯uvoxamine, whereas CYP1A2 seems to catalyze other less important pathways. Both the CYP2D6 and the CYP1A2 pathways seem to be saturated in parallel with increasinḡ uvoxamine dosage.

Some data indicate that bupropion inhibits the cytochrome P-450 enzyme CYP2D6, but very little published data is available on the extent of this inhibition. The objective of the present study was to quantify this inhibition in a subject treated with bupropion for smoking cessation. Genotypically, the patient was a CYP2D6 homozygous extensive metabolizer (EM). His CYP2D6 phenotype was assessed using the test drug dextromethorphan before, during, and after treatment with bupropion. During treatment with bupropion, he clearly changed from the EM to the poor metabolizer (PM) phenotype. Although the results from a single patient should be interpreted with great caution, the extent of the interaction indicates that bupropion might be a CYP2D6 inhibitor as potent as the most powerful CYP2D6 inhibitors known, such as quinidine and paroxetine.