Preclinical Pharmacokinetic Study Of A New Primaquine Prodrug
Rosangela Gonçalves Peccinini Principios Ativos Naturais e Toxicologia
São Paulo State University – UNESP
São Paulo, Brazil
Abstract:
The primaquine hematotoxicity is the major problem for its therapeutic use and this effect is aggravated by the frequent high doses administration to compensate for its low oral bioavailability. The structural modification of primaquine, in order to produce a prodrug, represents an alternative to modify thoroughly its pharmacokinetic profile with consequences on the drug plasmatic levels and on the toxic effects. Chung et al (1997) synthesized mutual prodrugs of primaquine using dipeptides as spacer agents, and the phenylalanine-alanine-primaquine (Phe-Ala-PQ) was selected to the preclinical pharmacokinetic study. In this work, the Phe-Ala-PQ pharmacokinetic profile was compared with the primaquine diphosphate profile. The study was carried out in male wistar rats (n=15) by intravenous and oral via. The primaquine plasmatic oscillations were smaller when the Phe-Ala-PQ was administered. The primaquine mean residence time (MRT) produced by oral Phe-Ala-PQ administration was significantly higher than the MRT of primaquine administered in diphosphate oral form. These results demonstrate that the conversion of the prodrug to the parent drug happens slowly and that the prodrug administration might maintain the primaquine levels for a larger period of time, and that the prodrug is a good candidate for further in vivo investigations.
Keywords: primaquine prodrug, pre clinical pharmacokinetics
