The effect of CYP2D6 genotype on the pharmacokinetics of lovastatin in Chinese subjects

To investigate whether specific CYP2D6 genotype can influence the pharmacokinetics of lovastatin, a drug with multi‐metabolic pathway (CYP3A4, 2C9, 2D6 and hydrolysis). A single 40 mg oral dose of lovastatin was administered to 19 healthy subjects. Multiple blood samples were collected over 24 h, and plasma concentrations of lovastatin and lovastatin acid (one of the major metabolites by hydrolysis) were determined by an LC‐MS‐MS method. CYP2D6 genotype was determined using PCR followed by restriction enzyme analysis or allele‐specific PCR tests. The subject distribution were: 4 homozygous CYP2D6*1 (*1/*1), 7 heterozygous CYP2D6*10 (*1/*10 or *2/*10) and 8 homozygous CYP2D6*10 (*10/*10) carriers. The area under the plasma concentration‐time curve (AUC 0–24 ) and terminal elimination half‐life (t 1/2 ) of lovastatin among the three groups were 12.4+4.0, 20.2+10.4 and 30.0+10.5 ng·h/ml, and 4.4+0.9, 6.0+2.4 and 8.1+2.5 h respectively (one‐way ANOVA, p=0.022 for AUC 0‐24 and p=0.046 for t 1/2 ). In comparison to the homozygous CYP2D6*1 carriers, the oral clearance of lovastatin were lower by 32.5% (p<0.05) and 55.2% (p<0.01) in the heterozygous CYP2D6*10 and homozygous CYP2D6*10 carriers respectively. The AUC 0‐24 of lovastatin acid also tended to be higher in the heterozygous CYP2D6*10 and homozygous CYP2D6*10 carriers; however, the difference was not statistically significant. These preliminary results in Chinese subjects show that among extensive metabolizers of CYP2D6, the pharmacokinetics of lovastatin appears to be dependent on CYP2D6 genotype. Clinical Pharmacology & Therapeutics (2004) 75 , P18–P18; doi: 10.1016/j.clpt.2003.11.067