Evaluation of permeability and bioavailability of a lead antileishmanial compound buparvaquone in animal models
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Date
2009
Authors
Venkatesh, Gantala
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Abstract
Leishmaniasis is a group of parasitic disease caused by the protozoan parasites of the
genus Leishmania and is currently endemic in 88 countries. This disease occurs in
two major forms, cutaneous and visceral leishmaniasis. Pentavalent antimonials are
the most widely used therapy for all forms of the disease. In in vitro and in vivo
studies buparvaquone (BPQ) has been found to be a promising lead compound for
the treatment of Leishmania donovani infections. The successful development of oral
drug delivery formulation for BPQ requires determination of the biopharmaceutical
properties mainly solubility and permeability. In preliminary stability studies, the test
samples of BPQ in methanol and acetonitrile form unknown degradation compounds
when exposed to the light and the rate of degradation was increased in the presence
of UV light. BPQ solubility studies were carried out in various standard buffer
solutions (pH 1.2 to 7 .5) and the solubility was found to be not more than 210 ng/ml.
BPQ was stable in both simulated gastric and intestinal fluids with < 5% degradation.
These results suggest that BPQ would be stable in the gastrointestinal tract prior to
absorption. Permeability of atenolol and propranolol were carried out in rat in situ
model at various concentrations of dimethyl sulfoxide (DMSO, 1-5% ). There was no
significant alteration (p>O.OS) in the mean values of the permeability markers. The
values agreed with previously t:eported permeability values. The results indicate that
the membrane integrity of the rat intestinal tissues was not affected by the presence
of up to 5% DMSO. Poorly water soluble drugs often cause difftoulties in
permeability studies due to their poor solubility limitation and non-specific
adsorption which lead to inaccurate estimation of permeability. Since BPQ is a
poorly water soluble compound the permeability study was carried out in the
presence of 5% DMSO as a co-solvent. The mean permeability value for BPQ was
0.912 xl04 cm/s indicating that it is a class II compound which is a highly permeable
and poorly water soluble compound according to the biopharmaceutical classification
system (BCS). Self-Microemulsifying drug delivery system (SMEDDS) is a feasible
oral formulation approach for BCS class II drugs since it increases their solubility
and bioavailability. Oral SMEDDS formulation development and screening was done
based on results obtained from solubility in various excipients, phase diagrams for
identifying microemulsification region, droplet size analysis and emulsification time.
In vitro dissolution and pharmacokinetic studies were performed with the optimized
formulation which is composed of Capryol 90 (9.82% w/w) and mixture of
Cremophor EL/Labrasol (4:1) (88.40% w/w) and BPQ (1.78% w/w). This
formulation yielded the smallest droplet size of 18 nm. Different RP-HPLC-UV
analytical methods were developed and validated for determining BPQ in the various
biological matrices. Bioavailability study of BPQ was conducted in healthy white
New Zealand male rabbits. Pharmacokinetic parameters were calculated for both i.v
and the optimized oral formulation of BPQ and the mean Cmax, T max and AUC (0-36)
were 999.83 ng/ml, 0.25 hour, 2872.71 ng.hour/ml and 171.74 ng/ml, 7.33 hour,
3456.38 ng.hour/ml respectively. Absolute bioavailability was found to be 40.10%.
Description
Keywords
Bioavailability , Antileishmanial , Buparvaquone