Evaluation of the influence of sex and CYP2C19 and CYP2D6 polymorphisms in the disposition of citalopram.
We investigate the impact of sex and genotype on citalopram disposition in 35 healthy volunteers who received an oral dose of 20mg citalopram within a single-dose bioequivalence study. CYP2C19*2 and *3, and CYP2D6*4 mutations were determined by Real-Time PCR. The influence of sex and genotype was analyzed by a linear mixed model for repeated measures, including formulation, period, sequence, sex, CYP2C19 and CYP2D6 as fixed effects and subject nested sequence*sex*CYP2C19*CYP2D6 as the random one. Pharmacokinetic parameters were log-transformed and AUC(infinity) and C(max) adjusted to the administered dose/weight. The model yields a statistical significance in AUC(infinity) and CL/F for CYP2C19 and CYP2D6. Gender, formulation, sequence or period effects were not statistically significant. AUC(infinity) of CYP2C19*1/*2 and CYP2C19*2/*2 carriers is 44% and 118% higher than wild type, respectively; CYP2D6 volunteers carrying 1/4 have an AUC 23% higher than wild type. Our data also suggest that the influence of CYP2D6 on AUC(infinity) is very low when it is in association with CYP2C19*1/*1 while its influence is more apparent in association with CYP2C19*1/*2. In conclusion, we demonstrate the influence of CYP2C19 and CYP2D6 in the disposition of citalopram, and we suggest that the influence of CYP2D6 is more probable in volunteers with at least one defective allele of CYP2C19.
Clinical Pharmacology Service, La Paz University Hospital, School of Medicine, Universidad Autónoma de Madrid, Paseo de La Castellana 261, 28046, Madrid, Spain. sfudio@gmail.com
Salvador
S
Fudio
Alberto M
AM
Borobia
Enrique
E
Piñana
Elena
E
Ramírez
Beatriz
B
Tabarés
Pedro
P
Guerra
Antonio
A
Carcas
Jesús
J
Frías
D000328:Adult; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D015283:Citalopram / Q000493:pharmacokinetics*; D065731:Cytochrome P-450 CYP2C19; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D008297:Male; D011110:Polymorphism, Genetic; D017367:Selective Serotonin Reuptake Inhibitors / Q000493:pharmacokinetics*; D012727:Sex Characteristics; D013810:Therapeutic Equivalency; D055815:Young Adult
D001189:Aryl Hydrocarbon Hydroxylases; D015283:Citalopram; D065731:Cytochrome P-450 CYP2C19; D019389:Cytochrome P-450 CYP2D6; D017367:Selective Serotonin Reuptake Inhibitors; C045793:CYP2C19 protein, human