Mass balance and metabolism of the antimalarial pyronaridine in healthy volunteers
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This was a single dose mass balance and metabolite characterization study of the antimalarial agent pyronaridine. Six healthy male adults were administered a single oral dose of 720 mg pyronaridine tetraphosphate with 800 nCi of radiolabeled 14C-pyronaridine. Urine and feces were continuously collected through 168 h post-dose, with intermittent 48 h collection periods thereafter through 2064 h post-dose. Drug recovery was computed for analyzed samples and interpolated for intervening time periods in which collection did not occur. Blood samples were obtained to evaluate the pharmacokinetics of total radioactivity and of the parent compound. Total radioactivity in urine, feces, and blood samples was determined by accelerator mass spectrometry (AMS); parent concentrations in blood were determined with LC/MS. Metabolite identification based on blood, urine, and feces samples was conducted using a combination of LC + AMS for identifying radiopeaks, followed by LC/MS/MS for identity confirmation/elucidation. The mean cumulative drug recovery in the urine and feces was 23.7 and 47.8 %, respectively, with an average total recovery of 71.5 %. Total radioactivity was slowly eliminated from blood, with a mean half-life of 33.5 days, substantially longer than the mean parent compound half-life of 5.03 days. Total radioactivity remained detectable in urine and feces collected in the final sampling period, suggesting ongoing elimination. Nine primary and four secondary metabolites of pyronaridine were identified. This study revealed that pyronaridine and its metabolites are eliminated by both the urinary and fecal routes over an extended period of time, and that multiple, varied pathways characterize pyronaridine metabolism.
KeywordsPyronaridine Mass balance Metabolism Antimalarial
The authors would like to thank James Settlage and Ann Hoffman for their contributions to this study through their work at Vitalea Science. This study was funded by Medicines for Malaria Ventures (MMV) and Shin Poong Pharmaceuticals.
Conflict of interest
Carrie Morris has nothing to disclose. Jang-Sik Shin is an employee of Shing Poong Pharmaceuticals. Stephan Duparc, Mark Baker, and Isabelle Borghini-Fuhrer are employees of MMV. Peter Lohstroh and Stephen Dueker are employees of Eckert & Ziegler Vitalea Science, which was paid by MMV for bioanalysis work. Donald Jung received personal fees from MMV for consultant work. Covance, Luis López-Lázaro’s and Rolf Pokorny’s employer at the time of the study, performed the study for MMV and received payments for it under a contract. Xing-Ping Fang and Li-Quan Wang are employees of XenoBiotic Laboratories Inc., which performed bioanalysis work under contract with MMV. Lawrence Fleckenstein reports receiving grants from MMV.
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