Pharmacokinetic interactions of Aloe vera gel polysaccharides with indinavir

Abstract

Aloe vera (L.) Burm.f. (Aloe barbadensis Miller) gel and whole leaf materials have shown the ability to modulate the bioavailability of vitamins and to change the transport of molecules across intestinal epithelia. In this study, precipitated polysaccharides from A. vera gel were separated into four different molecular weight fractions (MWF). This was done by means of membrane based centrifugal devices with specific molecular weight cut-off values (i.e. 300 kDa, 100 kDa, and 30 kDa). Chemical characterization of all the A. vera gel materials was done by means of nuclear magnetic resonance spectroscopy in order to quantify specific marker molecules such as aloverose, glucose and malic acid. Gel filtration chromatography linked to multi-angle laser-light scattering and refractive index detection was utilised to determine the average molecular weight of each fraction. The A. vera gel starting material used in this study contained all three marker molecules. Aloverose was present in different concentrations in all the aloe leaf gel materials investigated in this study except for the MWF that passed through the centrifugal device membrane with 30 kDa as molecular weight cut-off value. The aim of the study was to determine the effect of each polysaccharide fraction on drug transport and bioavailability. The effect of each of the A. vera gel materials was measured on the transepithelial electrical resistance (TEER) of Caco-2 cell monolayers as well as on the metabolism of indinavir in the LS180 cell model (both from intestinal epithelial origin). The precipitated polysaccharides decreased the TEER to a higher extent than the gel material, which indicated that the molecules responsible for opening of tight junctions are more concentrated in the precipitated material than in the gel material. The effect of the different MWF of the polysaccharides on the TEER did not correlate directly to their average molecular weight values. All of the aloe gel materials showed lower metabolite (M6) to parent drug (indinavir) ratio values when compared to that of the normal control group (indinavir alone), which represents an enzyme inhibition effect (albeit not statistically significantly). An in vivo bioavailability study of indinavir was done in Sprague-Dawley rats in the absence and presence of the various A. vera gel materials. Blood samples were analysed with a sensitive and selective liquid chromatography linked to mass spectrometry (LC-MS) method. The maximum indinavir plasma concentration (Cmax) values were increased by A. vera gel, crude precipitated polysaccharides and two of the MWF’s when compared to that of indinavir alone (control group). On the other hand, the area under the curve (AUC) values were increased by all the treatment groups. These changes represent relative bioavailability values of 1.28 for A. vera gel, 1.67 for crude precipitated polysaccharides, 1.84 for molecular weight fraction 1, 1.77 for molecular weight fraction 2, 1.39 for molecular weight fraction 3 and 1.95 for molecular weight fraction 4. The relatively high effect of the crude precipitated polysaccharides as well as two of the MWF’s on indinavir bioavailability correlates well with their in vitro performances in terms of TEER reduction and metabolism inhibition. The results from this study indicate modulation of indinavir bioavailability by A. vera gel materials, which was higher for the precipitated polysaccharides and some of the isolated polysaccharide fractions when compared to that of the A. vera gel material