Artemisinin and its derivatives represent an important class of antimalarials. In order to obtain new derivatives with a longer half-life and better bioavailability, the development of fluorinated analogues has received increasing attention. The purpose of this study was to investigate the permeation of artemisinin and of two fluoroalkyl derivatives of dihydroartemisinin (DHA), namely 10beta-(trifluoropropyloxy)dihydroartemisinin (F(1)-DHA) and 10-trifluoromethyl-16-[2-(hydroxyethyl)piperazine] (F(2)-DHA), across rat intestine using Ussing diffusion chambers. Further, the saturation solubility and partition coefficient of the compounds were determined in order to determine whether the substitution of hydrogen atoms by fluorine can induce great changes in these molecular properties. Artemisinin and F(2)-DHA permeability coefficients of 27.5 +/- 1.6 and 23.2 +/- 1.2 (x 10(-6), cm s(-1)), respectively, are predictive of good oral absorption. This indicates that the introduction of a fluoroalkyl group in a compound such as artemisinin in order to prolong its half-life does not constitute an obstacle for its absorption after oral administration. Moreover, the introduction of a polar substituent into the DHA structural scaffold increased the aqueous solubility of F(2)-DHA relative to artemisinin. F(1)-DHA permeability measurements showed low transepithelial diffusion across the intestinal mucosa. This indicates that the introduction of a fluorinated substituent at the alpha-methylene carbon of DHA ethers in order to provide protection against oxidative processes constitutes an obstacle for the absorption after oral administration.

Transport of fluoroalkyl dihydroartemisinin derivatives across rat intestinal tissue

BIGUCCI, FEDERICA;
2008

Abstract

Artemisinin and its derivatives represent an important class of antimalarials. In order to obtain new derivatives with a longer half-life and better bioavailability, the development of fluorinated analogues has received increasing attention. The purpose of this study was to investigate the permeation of artemisinin and of two fluoroalkyl derivatives of dihydroartemisinin (DHA), namely 10beta-(trifluoropropyloxy)dihydroartemisinin (F(1)-DHA) and 10-trifluoromethyl-16-[2-(hydroxyethyl)piperazine] (F(2)-DHA), across rat intestine using Ussing diffusion chambers. Further, the saturation solubility and partition coefficient of the compounds were determined in order to determine whether the substitution of hydrogen atoms by fluorine can induce great changes in these molecular properties. Artemisinin and F(2)-DHA permeability coefficients of 27.5 +/- 1.6 and 23.2 +/- 1.2 (x 10(-6), cm s(-1)), respectively, are predictive of good oral absorption. This indicates that the introduction of a fluoroalkyl group in a compound such as artemisinin in order to prolong its half-life does not constitute an obstacle for its absorption after oral administration. Moreover, the introduction of a polar substituent into the DHA structural scaffold increased the aqueous solubility of F(2)-DHA relative to artemisinin. F(1)-DHA permeability measurements showed low transepithelial diffusion across the intestinal mucosa. This indicates that the introduction of a fluorinated substituent at the alpha-methylene carbon of DHA ethers in order to provide protection against oxidative processes constitutes an obstacle for the absorption after oral administration.
F. Bigucci; T. Kamsu-Kom; C. Cholet; M. Besnard; D. Bonnet-Delpon; G. Ponchel
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11585/54766
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