J. TarningY. BergqvistN. P. DayJ. BergquistB. ArvidssonN. J. WhiteM. AshtonN. LindegårdhGoteborg University, Sahlgrenska AcademyHogskolan DalarnaMahidol UniversityNuffield Department of Clinical MedicineUppsala Universitet2018-08-202018-08-202006-12-01Drug Metabolism and Disposition. Vol.34, No.12 (2006), 2011-20191521009X009095562-s2.0-33751549060https://repository.li.mahidol.ac.th/handle/20.500.14594/23897Five metabolites of the antimalarial piperaquine (PQ) (1,3-bis-[4-(7- chloroquinolyl-4)-piperazinyl-1]-propane) have been identified and their molecular structures characterized. After a p.o. dose of dihydroartemisinin- piperaquine, urine collected over 16 h from two healthy subjects was analyzed using liquid chromatography (LC)/UV, LC/tandem mass spectrometry (MS/MS), Fourier transform ion cyclotron resonance (FTICR)/MS, and H NMR. Five different peaks were recognized as possible metabolites [M1, 320 m/z; M2, M3, and M4, 551 m/z (PQ + 16 m/z); and M5, 567 m/z (PQ + 32 m/z)] using LC/MS/MS with gradient elution. The proposed carboxylic M1 has a theoretical monoisotopic molecular mass of 320.1166 m/z, which is in accordance with the FTICR/MS (320.1168 m/z) findings. The LC/MS/MS results also showed a 551 m/z metabolite (M2) with a distinct difference both in polarity and fragmentation pattern compared with PQ, 7-hydroxypiperaquine, and the other 551 m/z metabolites. We suggest that this is caused by N-oxidation of PQ. The results showed two metabolites (M3 and M4) with a molecular ion at 551 m/z and similar fragmentation pattern as both PQ and 7-hydroxypiperaquine; therefore, they are likely to be hydroxylated PQ metabolites. The molecular structures of M1 and M2 were also confirmed using H NMR. Urinary excretion rate in one subject suggested a terminal elimination half-life of about 53 days for M1. Assuming formation rate-limiting kinetics, this would support recent findings that the terminal elimination half-life of PQ has been underestimated previously. Copyright © 2006 by The American Society for Pharmacology and Experimental Therapeutics.Mahidol UniversityPharmacology, Toxicology and PharmaceuticsArticleSCOPUS10.1124/dmd.106.011494