Volume 34, Issue 3 p. 262-265
Free Access

The effect of selective serotonin re-uptake inhibitors on cytochrome P4502D6 (CYP2D6) activity in human liver microsomes.

HK Crewe

HK Crewe

University Department of Medicine and Pharmacology, Royal Hallamshire Hospital, Sheffield.

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MS Lennard

MS Lennard

University Department of Medicine and Pharmacology, Royal Hallamshire Hospital, Sheffield.

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GT Tucker

GT Tucker

University Department of Medicine and Pharmacology, Royal Hallamshire Hospital, Sheffield.

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FR Woods

FR Woods

University Department of Medicine and Pharmacology, Royal Hallamshire Hospital, Sheffield.

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RE Haddock

RE Haddock

University Department of Medicine and Pharmacology, Royal Hallamshire Hospital, Sheffield.

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First published: September 1992
Citations: 339

Abstract

Inhibition of human cytochrome P4502D6 (CYP2D6)-catalysed metabolism can lead to clinically significant alterations in pharmacokinetics. Since there is evidence that the selective serotonin reuptake inhibitor (SSRI) class of antidepressant drugs might inhibit CYP2D6, the effects of five SSRIs on human liver microsomal CYP2D6 activity were compared with each other and with three tricyclic antidepressant drugs. On a molar basis, paroxetine was the most potent of the SSRIs at inhibiting the CYP2D6-catalysed oxidation of sparteine (Ki = 0.15 microM), although fluoxetine (0.60 microM) and sertaline (0.70 microM) had Ki values in the same range. Fluvoxamine (8.2 microM) and citalopram (5.1 microM) also inhibited CYP2D6 activity. The major circulating metabolites of paroxetine in man produced negligible inhibition. In contrast, norfluoxetine the active metabolite of fluoxetine, was a potent CYP2D6 inhibitor (0.43 microM). CYP2D6 activity was also diminished by the tricyclic antidepressant drugs clomipramine (2.2 microM), desipramine (2.3 microM) and amitriptyline (4.0 microM). These findings suggest that compounds with SSRI activity are likely to interact with human CYP2D6 in vivo with the potential of causing drug interactions.