AIMS:To determine CYP2C19 and CYP2D6 activity in patients with multiple sclerosis (MS) before and during interferon (IFN)-beta treatment. METHODS:CYP2C19 and CYP2D6 activities were assessed using the probe drugs mephenytoin and debrisoquine, respectively. Urinary mephenytoin (S/R) and debrisoquine (debrisoquine/hydroxy-debrisoquine) metabolic ratios (MR) were determined in 10 otherwise healthy Caucasian multiple sclerosis (MS) patients in the initial stage of the disease, prior to and 1 month after commencing treatment with IFN-beta (Avonex, Rebif or Betaferon). In addition, CYP2C19*2, CYP2C19*3, CYP2D6*3, CYP2D6*4, and CYP2D6*5 genotyping was performed. RESULTS:There was no significant difference in the (S)/(R) mephenytoin ratio (mean difference 0.04; 95% CI -0.03, 0.11) or the debrisoquine MR (mean difference 0.29; 95% CI -0.44, 1.02) before and during regular IFN-beta treatment in extensive metabolizers (EM) (P = 0.5 and P = 0.4 for the respective probe drugs; n = 9 subjects). There were also no differences between the different IFN-beta treatments (P = 0.6 for the (S)/(R) mephenytoin ratio and P = 0.7 for the debrisoquine MR; anova; n = 10). CONCLUSIONS:IFN-beta treatment did not affect the activity of CYP2C19 or CYP2D6. The results suggest that it is safe to administer CYP2C19 or CYP2D6 substrates, without dose adjustment, to patients treated with IFN-beta.