CYP2D6 INHIBITION IN PATIENTS TREATED WITH SERTRALINE

Sertraline, a selective serotonin reuptake inhibitor used to treat dep ression, inhibits CYP2D6 in vitro (Ki = 1.2 mu M) less potently than f luoxetine (Ki = 0.15 mu M). To determine the extent and time course of CYP2D6 inhibition in patients, six males (mean age: 40 years, range: 29-64 years), who were starting treatment for depression with sertrali ne, were phenotyped on five occasions (once before treatment and appro ximately 3, 7, 14, and 21 days later). Phenotype status was determined using oral dextromethorphan (30 mg) by calculating the urinary ratio of O-demethylated metabolites to parent drug (i.e., log ODMR). CYP2D6 genotype was determined by leukocyte DNA analysis using polymerase cha in reaction amplification. Compliance was confirmed by sertraline plas ma levels. Daily sertraline dosages ranged from 50 to 150 mg. Genotype results indicated all subjects were extensive metabolizers (four homo zygous wild type [wt], two heterozygous wt/B mutation). Phenotype resu lts showed that CYP2D6 inhibition in patients treated with sertraline appeared to be related to baseline CYP2D6 activity and sertraline dosa ge. Some patients with high CYP2D6 activity can demonstrate inhibition with sertraline dosages as low as 50 mg.