Paroxetine Pharmacokinetics and Its Adverse Effects in Korean Healthy Volunteers; Relation to Metoprolol Metabolic Ratio and Genotype

초록

We evaluated the paroxetine pharmacokinetics and its adverse effects, and assessed their relationships with metoprolol MR and genotype in 16 healthy Korean subjects (EM;15, PM;1) who showed various metoprolol MR(range: 0.07-17.7), and 3 genotype groups related to CYP2D6* 10B allele (6 homozygous for the wt allele, 6 heterozygous for the CYP2D6* 10B allele, 4 homozygous for the CYP2D6* 10B allele). Blood samples were drawn serially up to 240hrs after single 40mg dose of paroxetine and side effects were observed throughout the study period. Plasma paroxetine concentrations were measured by HPLC and pharmacokinetic parameters were estimated using noncomparmental analysis. Mean oral clearance (CL/F) was 2.30±1.78 L/kg/hr in EM group and 0.15 L/kg/hr in one PM, and they were well correlated with metoprolol MR(r=0.64, p<0.05). Mean value of AUC was 548.10±585.05 ng/ml/hr in EM group and 4554.05 ng/ml.hr in PM, and it showed best of volume of distribution (Vd/F_ was 41.78±25.89 L/kg in EM and 14.88 L/kg in a PM. The oral clearance and AUC of paroxetine showed significant difference between CYP2D6 wt-allele homozygous, CYP2D6* 10B-allele hoterozygous and homozygous groups (p<0.05). The duration of side effects was well correlated with metoprolol MR (r=0.60, p<0.05) and AUC (r=0.60, p<0.05) of paroxetine in subjects who complained various side effects. These results suggested that motoprolol phenotype and CYP2D6 genotype would be important factors to determine the pharmacokinetics and even development of adverse effects of paroxetine in an individual patient taking drug.