Identification of a novel CYP2C19-mediated metabolic pathway of S-citalopram in vitro.
Systemic exposure of the antidepressant S-citalopram (escitalopram, SCIT) differs several-fold according to variable cytochrome P450 2C19 activity, demonstrating the importance of this enzyme for the metabolic clearance of SCIT in vivo. However, previous studies have indicated that the involvement of CYP2C19 in formation of the metabolite N-desmethyl S-citalopram (SDCIT) is limited. Therefore, the purpose of the present in vitro study was to investigate to what extent the CYP2C19-mediated clearance of SCIT was due to a metabolic pathway different from N-desmethylation and to identify the product(s) of this possible alternative metabolic reaction. CYP2C19-mediated metabolism of SCIT was investigated using recombinant Supersomes expressing human CYP2C19. Initial experiments showed that approximately half of the CYP2C19-mediated clearance of SCIT was accounted for by the N-desmethylation pathway. Subsequent experiments identified that, in addition to SDCIT, the propionic acid metabolite of SCIT (SCIT PROP) was formed by CYP2C19 in vitro. Formation of SCIT PROP accounted for 35% of total CYP2C19-mediated clearance of SCIT (calculated as the ratio between metabolite formation rate and substrate concentration at low substrate concentration). Moreover, analysis of samples from six CYP2C19-genotyped patients treated with SCIT indicated that differences in serum concentrations of SCIT between CYP2C19 genotypes may be due to a combined effect on SCIT PROP and SDCIT formation. Identification of SCIT PROP as a metabolic pathway catalyzed by CYP2C19 might explain why impaired CYP2C19 activity has a substantially larger effect on SCIT exposure than estimated from in vitro data based solely on formation of SDCIT.
Rudberg
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I
Department of Psychopharmacology, Diakonhjemmet Hospital, N-0319 Oslo, Norway. idarudberg@gmail.com
Reubsaet
J L E
JL
Hermann
M
M
Refsum
H
H
Molden
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E
D000328:Adult; D018687:Antidepressive Agents, Second-Generation / Q000097:blood / Q000378:metabolism*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism*; D001711:Biotransformation; D015283:Citalopram / Q000031:analogs & derivatives / Q000097:blood / Q000378:metabolism*; D065731:Cytochrome P-450 CYP2C19; D003640:Dealkylation; D005260:Female; D005838:Genotype; D006801:Humans; D007700:Kinetics; D008297:Male; D008861:Microsomes / Q000201:enzymology; D008875:Middle Aged; D008954:Models, Biological; D010641:Phenotype; D011422:Propionates / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000097:blood / Q000378:metabolism*
D018687:Antidepressive Agents, Second-Generation; D001189:Aryl Hydrocarbon Hydroxylases; D015283:Citalopram; D065731:Cytochrome P-450 CYP2C19; D011422:Propionates; D011994:Recombinant Proteins; D017367:Selective Serotonin Reuptake Inhibitors; C046304:desmethylcitalopram; C045793:CYP2C19 protein, human