[Covalently bound residues: theoretical aspects]

Covalently bound residues (CBRs) result from the covalent binding of the parent drug or its metabolites to endogenous macromolecules. They are not extractable from the tissues by exhaustive extraction, denaturation and solubilization techniques, and are not the result of endogenous incorporation. They can be detected in the non-extractable radioactivity which persists in tissues after administration of radiolabeled drugs. The characteristics of CBRs are discussed. Covalent binding is an association of a reactive metabolite (electrophile or free radicals) and endogenous molecules (proteins, lipids). This chemical reaction is non-specific and irreversible. Even if the covalent bond is cleaved, the compound released will not be the highly reactive intermediate metabolite. The covalently bound metabolites can have a potential toxic effect in the target species but they probably represent low toxicity for consumers. Pharmacokinetic analyses of CBRs have demonstrated their specific properties: 1) they make up the largest fraction of late residues, and 2) their bioavailability is low. Several examples are given to support these concepts.