Effect of CAR polymorphism on the pharmacokinetics of artemisinin in healthy Chinese subjects

Repeated pretreatment with the antimalarial drug artemisinin (QHS) could lead to reduced exposure to the parent drug, which is mainly mediated by auto-induction of CYP2B6 activity. CYP2B6 is most sensitive to the inductive effect of constitutive androstane receptor (CAR), which can be activated by QHS. CYP2B6 polymorphism has no influence on pharmacokinetics of QHS derivatives. This study aimed to investigate the effect of CAR (C540T) polymorphism on the auto-induction metabolism-mediated pharmacokinetics of QHS. Healthy Chinese subjects (six in each group with the genotypes of CAR 540C/C, 540C/T and 540T/T; all carrying the CYP2B6*1*1 genotype) received a recommended two-day oral doses of QHS-piperaquine (PQ) to assess the pharmacokinetics of QHS and its metabolite deoxyartemisinin (DQHS). The exposures to QHS and DQHS were significantly lower (p < 0.05) in subjects homozygous for the CAR 540T/T genotype than those with the 540C/C genotype after the repeated dose. QHS did not show different induction clearance in subjects homozygous for the 540C/C genotype (1.3-fold), compared with those carrying the heterozygous 540C/T (2.1-fold) or homozygous 540T/T (1.7-fold) genotype. In conclusion, the CAR (C540T) genotype contributed to the interindividual variability of QHS pharmacokinetics, and the dose regimen for QHS deserves further evaluation especially in specific populations.