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Characterising Fluvoxamine Metabolism

Cytochrome P450 (CYP) 2D6 does not seem to play an important role in fluvoxamine metabolism, but sub-therapeutic fluvoxamine doses inhibit CYP1A2 and CYP2C19.

Both CYP1A2 (which is induced by smoking) and CYP2D6 metabolise fluvoxamine. The CYP2D6 phenotype stratifies into extensive and poor debrisoquin metabolizers. Caffeine and omeprazole offer probes for CYP1A2 and CYP2C19 respectively.

Against this background, researchers from the Karolinska Institute, Stockholm and University of Extremadura, Badajoz, Spain, treated five poor metabolizers with a single 25 mg oral dose of fluvoxamine, followed by 25 mg daily for a week. Five extensive metabolizers received 50 mg both as a single dose and for a week. On day six, both groups received 100 mg caffeine and, a day later, 20 mg omeprazole. After wash out, the study was repeated using 10 and 20 mg fluvoxamine for poor and extensive metabolizers respectively.

Fluvoxamine kinetics following the single oral doses did not differ significantly between extensive and poor metabolizers. At the higher steady-state fluvoxamine dose, poor metabolizers showed lower clearance than extensive metabolizers. This difference did not emerge at lower doses. At steady state, the higher fluvoxamine doses inhibited CYP1A2 and CYP2C19 by approximately 75 to 80 per cent. The inhibition with the lower doses was around 40 to 50 per cent.

Caffeine's area under the plasma concentration-versus-time curve between 0 and 24 hours increased five and two-fold after the higher and lower fluvoxamine doses respectively. The area under the plasma concentration-time curve between zero and eight hours for the 5-hydroxyomeprazole/omeprazole ratio declined by 3.4 and 2.4 fold respectively.

The authors added that one extensive metabolizer showed very low fluvoxamine clearance after the single dose and at steady state. The researchers speculated that the patient might express deficient gastrointestinal transporter protein. This could increase fluvoxamine absorption.

The authors concluded that there is "no convincing evidence" that CYP2D6 plays an important role in fluvoxamine metabolism. However, sub-therapeutic fluvoxamine doses inhibit caffeine and omeprazole metabolism. Indeed, they commented that fluvoxamine's inhibition of CYP1A2 and CYP2C19 cannot be separated, even at low doses.
Clin Pharmacol Ther 2002;71:141-52. "Low daily 10-mg and 20-mg doses of fluvoxamine inhibit the metabolism of both caffeine (cytochrome P4501A2) and omeprazole (cytochrome P4502C19)"

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