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Key principles of conjugation: All six pathways require specific cofactors (nutrient deficiencies directly impair detoxification) Competition exists between pathways when a single substrate can be conjugated by more than one enzyme Conjugation does not always produce a less toxic product (some sulfation and acetylation reactions generate reactive metabolites) Conjugated products must still be transported out of the cell via Phase III transporters (MRP, P-gp, BCRP) for excretion R Bile is the primary excretion route for large, glucuronidated, and glutathione-conjugated metabolites Urine handles smaller, sulfated and acetylated conjugates The balance between Phase I activation and Phase II conjugation is critical

CMS reviews proposals on a case-by-case basis to determine alignment with Medicaid and federal policies (which we note tend to shift with each administration)

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Blood work, urine testing and a physical exam are needed to determine whether or not you are getting enough nutrients