Description:

Chemosynthetic Livers: Predict, Prepare and Prove the Structure, Activity and Toxicity of Drug Metabolites

Abstract:
We report advances in proprietary in vitro green chemistry-based technology, mimicking in vivo metabolism of several chemical entities used in pharmaceuticals, cosmetics, and agrochemicals. Biomimiks™ enables prediction of metabolism patterns and introduces new paradigms for drug discovery and drug-drug interactions for clinical diagnostics. Metabolites are implicated in adverse drug reactions, and are the subject of intense scrutiny in drug R&D. Present-day processes involving animal studies are expensive, labor-intensive and chemically inconclusive. Our catalysts (azamacrocycles) are sterically protected and electronically activated, providing speed, stability and scalability. We predict structures of metabolites, prepare them on a large scale by oxidation, and elucidate chemical structures. Comprehensive safety evaluation enables scientists to conduct more complete in vitro metabolism studies, confirm structure and generate quantitative measures of toxicity. Biomimiks™ is an animal-free platform that identifies a more complete set of safety-relevant drug metabolites while keeping up with the rapid pace of drug development. Polypharmacy, involving co-administration of several drugs, is common among the elderly and chronically ill.  It is a risk factor for adverse drug reactions (ADRs) and drug-drug interactions (DDIs). One plausible DDI occurs when a drug interferes with another, causing irreversible changes to formation of metabolites from one or both. Such suppression or attenuation of metabolism could cause variances in toxicity and efficacy. We report experiments to predict and confirm modulation of oxidative metabolites from several combinations of common drugs for cancer, diabetes, hypercholesterolemia and hypertension in the presence of each other. Recent papers indicate best evidence for the dimerization of some compounds in dilute aqueous solution or assorted complex formation between disparate compounds.