Characterization of human urinary metabolites of the antimalarial piperaquine

dc.contributor.authorJ. Tarningen_US
dc.contributor.authorY. Bergqvisten_US
dc.contributor.authorN. P. Dayen_US
dc.contributor.authorJ. Bergquisten_US
dc.contributor.authorB. Arvidssonen_US
dc.contributor.authorN. J. Whiteen_US
dc.contributor.authorM. Ashtonen_US
dc.contributor.authorN. Lindegårdhen_US
dc.contributor.otherGoteborg University, Sahlgrenska Academyen_US
dc.contributor.otherHogskolan Dalarnaen_US
dc.contributor.otherMahidol Universityen_US
dc.contributor.otherNuffield Department of Clinical Medicineen_US
dc.contributor.otherUppsala Universiteten_US
dc.description.abstractFive 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.en_US
dc.identifier.citationDrug Metabolism and Disposition. Vol.34, No.12 (2006), 2011-2019en_US
dc.rightsMahidol Universityen_US
dc.subjectPharmacology, Toxicology and Pharmaceuticsen_US
dc.titleCharacterization of human urinary metabolites of the antimalarial piperaquineen_US