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

Background: Artequick 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.

Methods: Fourteen 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.

Results: Four 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 AUC0-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 AUC0-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.

Conclusions: The 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.

Figure 1

Structures of phase I (Deoxy-QHS, M1-M3) and phase II (M4, M5) metabolites of artemisinin (QHS) detected in human plasma, and proposed metabolic pathways for QHS.

Figure 2

Representative full-scan chromatograms of (A) a blank human plasma sample spiked with IS (ARM, 1 μM); (B) a blank human plasma sample spiked with artemisinin (QHS; 17.7 nM), deoxyartemisinin (Deoxy-QHS; 18.8 nM), and IS (ARM, 1 μM); and (C) a human plasma sample at 1.25 h after a single oral dose of QHS (1.8 mg/kg). I: QHS and monohydroxylated deoxyartemisinin (m/z 283.1540); II: deoxyartemisinin (deoxy-QHS; m/z 284.1856); III: monohydroxylated artemisinin (m/z 316.1775); IV: dihydroxylated artemisinin (m/z 332.1704) V: the glucuronide of monohydroxylated deoxy-QHS M5 (m/z 476.2126); VI: the glucuronide of monohydroxylated QHS (m/z 492.2076); VII: IS (ARM, m/z 316.2118).

Figure 3

Mean (+SD) plasma concentration-time profiles of artemisinin (QHS) and its phase I metabolites (deoxyartemisinin: Deoxy-QHS; monohydroxylated deoxy-QHS: M1; monohydroxylated QHS: M2; dihydroxylated QHS: M3) in healthy Chinese (n = 14 each) following two consecutive days of oral doses of QHS (1.8 mg/kg).

Figure 4

Individual values for AUC ratio of phase I metabolites (M1-M3 and deoxy-QHS) of artemisinin (QHS) to the parent drug in healthy Chinese (n = 14 each) following one-day or two-day oral doses of QHS (1.8 mg/kg).

Figure 5

Mean (+SD) plasma concentration-time profiles of phase II metabolites of artemisinin (QHS) (the glucuronide of monohydroxylated deoxy-QHS: M4; the glucuronide of monohydroxylated QHS: M5) in healthy Chinese (n = 14 each) following two consecutive days of oral doses of QHS (1.8 mg/kg).

Figure 6

Individual values for AUC ratio of phase II metabolites (M4 and M5) to their respective hydroxylated metabolites (M1, M2) of artemisinin (QHS) in healthy Chinese (n = 14 each) following one-day or two-day oral doses of QHS (1.8 mg/kg).