Auto-induction of phase I and phase II metabolism of artemisinin in healthy Chinese subjects after oral administration of a new artemisinin-piperaquine fixed combination

Abstract

BackgroundArtequick is a relatively inexpensive artemisinin (Qing-hao-su; QHS)-based combination therapy (ACT) that contains QHS and piperaquine (PQ), which has not been widely used because of the decreased concentration level of QHS after repeated oral administrations for five to seven days as a monotherapy. This study was designed to evaluate the potential auto-induction metabolism of QHS in healthy Chinese adults after a two-day oral administration of QHS-PQ. The effect of QHS-PQ on the activity of the CYP2B6 and CYP3A4 was also investigated.MethodsFourteen healthy Chinese subjects received two-day oral doses of QHS-PQ (Artequick). A two-drug cocktail consisting of bupropion and midazolam was used to assess the activities of CYP2B6 and CYP3A, respectively. Plasma samples were analysed for QHS and its phase I/II metabolites, probe drugs and their metabolites, using a validated liquid chromatography tandem mass spectrometric (LC-MS) method.ResultsFour major phase I metabolites of QHS (M1-M3 and deoxy-QHS) and two subsequent phase II metabolites (M4-M5) were detected in human plasma after oral administrations of QHS-PQ. The AUC 0-t of the QHS and its phase I metabolites decreased significantly (P < 0.05) with increased oral clearance (CL/F) after two-day oral doses of QHS-PQ, whereas its phase II metabolites exhibited higher AUC (P < 0.01). The phase I metabolic capability, calculated by the AUC 0-t ratio of all phase I metabolites to QHS, increased 1.5-fold after the repeated dose (P < 0.01), and the phase II metabolic capability increased 1.5-fold for M4 and 3.0-fold for M5. The enzyme activity of CYP2B6 and CYP3A4 increased 2.1-fold and 3.2-fold, respectively, after two-day oral doses of QHS-PQ.ConclusionsThe auto-induction of both phase I and phase II metabolism of QHS was present in healthy Chinese subjects after a recommended two-day oral dose of QHS-PQ. The auto-induction metabolism also existed for phase I metabolites of QHS. The enzyme activity of CYP2B6 and CYP3A4 was induced after the two-day oral doses of QHS-PQ. Based on these results, the alternative common three-day regimen for QHS-PQ could probably lead to lower bioavailability of QHS and higher potential of drug-drug interaction caused by the induction of drug-metabolizing enzymes.

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

“…[1][2][3]13) These findings suggest that PQ should not influence the pharmacokinetic characteristics of QHS when co-administered in the proposed fixed oral combination. 13) The change of QHS exposure and clearance was supposed to be the contribution of QHS in the present study.…”

“…The sample preparation, chromatographic and mass spectrometric conditions were shown in a previous report. 3) Pharmacokinetic analysis: The peak plasma concentration (C max ) and the time to C max (T max ) were obtained from experimental observations. The area under the plasma concentration-time curve (AUC o-t ) was calculated using the linear trapezoidal rule to approximately the last point.…”

“…QHS has not been used to a great extent in ACT because of its low bioavailability and time-dependent pharmacokinetics, which have been confirmed in healthy volunteers and infected patients as a several-fold decrease in plasma concentration of QHS with a corresponding increase in oral clearance after repeated oral administrations for several days. [1][2][3] The auto-induction metabolism has been suggested for this time-dependency. 4,5) The elimination of QHS is mediated primarily by CYP2B6, with a probably secondary contribution of CYP3A and CYP2A6.…”

“…6,7) QHS appears to induce several enzymes including CYP2B6. 3,5) CYP2B6 is most sensitive to the inductive effect of constitutive androstane receptor (CAR), which can be activated by QHS. 8,9) The human genes coding for CYP2B6 and CAR are highly polymorphic, 10,11) which could probably lead to interindividual variability in QHS pharmacokinetics, auto-induction metabolism and response to treatment.…”

The effect of UGTs polymorphism on the auto-induction phase II metabolism-mediated pharmacokinetics of dihydroartemisinin in healthy Chinese subjects after oral administration of a fixed combination of dihydroartemisinin-piperaquine

“…Artemisinin drugs (Qing-hao-su and artemether,) showed time-dependent pharmacokinetics in both healthy volunteers and infected patients as a several-fold decrease in plasma concentration of the parent drug with a corresponding increase in oral clearance after repeated oral administrations [ 11 , 12 ]. However, DHA and artesunate showed less convincing evidence for this time-dependency [ 13 – 15 ].…”