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The effect of selective serotonin
re-uptake inhibitors on cytochrome P4502D6 (CYP2D6) activity in human
liver microsomes.
Crewe HK, Lennard MS, Tucker GT,
Woods FR, Haddock RE.
University Department of Medicine and
Pharmacology, Royal Hallamshire Hospital, Sheffield.
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.
PMID: 1389951 [PubMed -
indexed for MEDLINE]
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