A method for high-throughput Caco-2 permeability screening of drug candidates has been developed using thirteen generic drugs as test compounds. The high throughput was achieved by either a sample pooling or a cassette dosing approach, along with the use of a rapid, simple and sensitive direct injection/on-line guard cartridge extraction/tandem mass spectrometric assay that was also developed in this study. It was of concern that possible drug-drug interactions (e.g., inhibition of P-glycoprotein-mediated transport of a drug by another, and/or competition of the drugs for transport pathways), when the cassette dosing regimen was implemented, may give rise to inconsistent results compared with those attained by a traditional single-drug dosing approach. However, the apparent permeability coefficients of the test drugs across Caco-2 monolayers measured by the sample pooling or cassette dosing (up to five drugs co-administered in this study) strategy were in good conformity with the data obtained by single-drug dosing followed by discrete sample analysis.

Abstract:The presence of a neurotoxic amino acid, 3-N-oxalyl-~-2,3-diaminopropanoic acid (8-ODAP), in the seeds of grass pea (Lalhyrus satiuus) is the cause of an irreversible spastic paraparesis, neurolathyrism, after overconsumption. This is a negative factor in an otherwise very tasty, nutritious, easily cultivated and hardy food crop in Asia and Africa. The reduction of 8-ODAP to less than 10% of the original content has been reached by fermenting L satiuus Jamalpur seeds with Aspergillus oryzae NRRL 1988 for 48 h, followed by fermentation with Rhizopus oligosporus sp T-3 for 48 h. Other nutritional qualities were also improved in the fermented seed meal : increased content of protein, higher amino acid scores for sulphur-containing and aromatic amino acids, better resistance to high temperature and to oxidation, and drastic reduction of the flatulence factors.

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The major toxin present in the dry seeds and seedlings of Lathyrus sativus is the neurotoxin 3-N-oxalyl-L-2,3-diaminopropanoic acid (beta-ODAP). The presence of one additional neurotoxin and an osteotoxin in the seedlings increases the overall toxicity. Isolation, purification, and detection of these toxins are described.