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Multiple-dose pharmacokinetics of a novel, synthetic trioxane-antimalarial compound 97/78 in rats using LC-MS/MS method

Rajendra Pratap Singh, Sabarinath S., Hari Narayan Kushwaha, Nagsen Gautam, Ram Chandra Gupta, Shio Kumar Singh*


Multiple dose pharmacokinetic study was studied in rats following oral dose administration at 47 mg/kg. The pharmacokinetic profile of 97/78 was investigated in form of its completely converted in-vivo active metabolite 97/63 after dose administration. Quantification of metabolite 97/63 in rat plasma was achieved on LC-MS/MS. Chromatographic run time was 4.0 min and the weighted (1/x2) calibration curves were linear over the range 1.56–200ng/ml. After oral administration of 97/78 in rats the peak plasma concentration was observed between 0.75 and 2 h. Compound was rapidly absorbed and declined within 24 h after each dosing.  Multiple maximum concentrations were observed at different time points. Mean Residence Time of 97/63 was observed at 5.06±0.40 h. The terminal elimination half-lives did not significantly change for multiple doses (T1/2, 2.65±0.70 h) in comparison to single-dose (T1/2, 2.80±0.56 h) administration. Also there is no enhancement in AUC values during multiple dose administration, indicating no plasma accumulation of 97/63. There were no significant differences between peak and trough concentrations of 97/63 on days 1, 2, 3, 4 and 5. Trough plasma concentration states that the body systemic exposure is high. The average plasma concentration-time profile of 97/63 confirms no plasma accumulation of 97/63.


Antimalarial; LC-MS/MS; Multiple-dose; 97/78; Pharmacokinetics

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