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

Abstract

BackgroundDihydroartemisinin (DHA) is a component of artemisinin-based combination therapy (ACT), which is widely recommended for treatment of uncomplicated falciparum malaria. DHA is also the main metabolite of artemether and artesunate, both of which are used in ACT. Due to auto-induction metabolism, declining plasma concentrations after the repeated dosing have been reported for artemisinin (Qing-hao-su) and artemether. This study was designed to evaluate the potential auto-induction metabolism of DHA in healthy Chinese adults after multiple oral doses of DHA. The polymorphic effects of UGT1A9 (I399C>T) and UGT2B7*2 (802C>T), the major enzymes involved in the metabolism of DHA, on the pharmacokinetic profiles of DHA and its metabolite was also studied.MethodsSixteen healthy Chinese subjects (four I399TT/802CC, four I399CC/802TT, four I399TT/802TT and four I399CT/802CT) received four recommended oral doses of Artekin, an ACT containing DHA (80 mg/dose) and piperaquine (PQ; 640 mg/dose), at 0, 6, 24 and 32 h. Plasma samples were analysed for DHA and its metabolite using a validated liquid chromatography tandem mass spectrometric (LC-MS) method.ResultsDHA and its glucuronidated metabolite DHA-Glu were detected in human plasma after oral administration of DHA-PQ. Compared with the first dose, the AUC0-t of the parent drug DHA decreased significantly (P<0.01) with increased oral clearance (CL/F) after each repeated dose of DHA-PQ, whereas its metabolite DHA-Glu did not change (P>0.05) in AUC0-t or Cmax. The phase II metabolic capability, calculated by the AUC0-t ratio of DHA-Glu to the parent drug DHA, increased 1.5-fold (90% CI, 1.3-1.7), 1.2-fold (90% CI, 1.1-1.3) and 1.7-fold (90% CI, 1.5-1.8) after the second, third and fourth dose, respectively. No polymorphic effect was found for UGT1A9 (I399C>T) and UGT2B7*2 (802C>T) on the pharmacokinetic profiles of DHA and its metabolite DHA-Glu.ConclusionsThe auto-induction phase II metabolism of DHA was present in healthy Chinese subjects after the recommended two-day oral doses of DHA-PQ (Artekin). The metabolic capability could recover after a 12-h dosing interval, which suggested that the alternative common three-day regimen (once daily) for DHA-PQ could probably lead to higher bioavailability of DHA. The polymorphism of UGT1A9 (I399C>T) and UGT2B7*2 (802C>T) may not be a concern during the treatment with DHA.Electronic supplementary materialThe online version of this article (doi:10.1186/1475-2875-13-478) contains supplementary material, which is available to authorized users.

Toward New Transmission-Blocking Combination Therapies: Pharmacokinetics of 10-Amino-Artemisinins and 11-Aza-Artemisinin and Comparison with Dihydroartemisinin and Artemether

“…1 ) have been in use since their introduction by the Chinese in the 1970s and 1980s ( 31 – 33 ). These, including DHA, are inducers of their own metabolism ( 34 – 36 ) and elicit neurotoxicity concerns ( 29 , 37 – 40 ). DHA is thermally unstable and in aqueous solution readily rearranges to a peroxyhemiacetal ( 41 – 45 ) whose formation also may intrude during preparation and storage of DHA ( 45 ).…”

Identification and disposition of novel mono‐hydroxyl mefenamic acid and their potentially toxic 1‐O‐acyl‐glucuronides in vivo

“…In a recent clinical study, auto‐induced glucuronidation was observed in healthy subjects receiving multiple oral doses of a UGT1A9 and UGT2B7 substrate, dihydroartemisinin . Coincidently, the AUC 0→t ratio of dihydroartemisinin glucuronides to the parent dihydroartemisinin also increased by 1.7‐fold in that study . Nevertheless, it should be noted that not all glucuronides of MEF follow an auto‐induction mechanism.…”

“…Auto‐induction of UGT activities following repeated treatment of UGT substrates, especially those involving UGT1A9 and UGT2B7 (which are the major enzymes responsible for the glucuronidation of MEF) may be one possible mechanism that accounts for the increased systemic exposure of MEFG . In a recent clinical study, auto‐induced glucuronidation was observed in healthy subjects receiving multiple oral doses of a UGT1A9 and UGT2B7 substrate, dihydroartemisinin . Coincidently, the AUC 0→t ratio of dihydroartemisinin glucuronides to the parent dihydroartemisinin also increased by 1.7‐fold in that study .…”

Population Pharmacokinetics of Artemether, Dihydroartemisinin, and Lumefantrine in Rwandese Pregnant Women Treated for Uncomplicated Plasmodium falciparum Malaria

“…CYP3A4 plays the largest role in ARM metabolism in vitro ( 31 , 32 ). DHA is eliminated subsequently by glucuronidation, most likely mediated by UGT1A9 and UGT2B7 ( 31 , 33 ). Autoinduction of hepatic clearance can be modeled in many ways, but the enzyme turnover model implemented for ARM in this study is in line with the assumption that the ARM concentration affects only ARM clearance and not the clearance of DHA, i.e., inhibition of metabolite formation ( 34 ).…”