title: Predictability of the covalent binding of acidic drugs in man.
abstract: Although metabolism via glucuronide conjugation has generally been considered a detoxification route for carboxylic acids, the newly discovered chemical reactivity of these conjugates, leading to covalent binding with proteins, is consistent with the toxicity observed for drugs containing the carboxylic acid moiety. Here we report that degradation rates (intramolecular rearrangement and hydrolysis) for 9 drug glucuronide metabolites show an excellent correlation (r2 = 0.995) with the extents of drug covalent binding to albumin in vitro. Furthermore, this binding capacity is predictable based on chemical structure of the acid and depends on the degree of substitution at the carbon alpha to the carboxylic acid. The in vivo covalent binding in humans for these drugs is also predictable (r2 = 0.873) when the extent of adduct formation is corrected for the measured plasma glucuronide concentrations. These results suggest that the structure of a carboxylic acid drug may predict the degree to which the corresponding acyl glucuronides will form covalent adducts that probably/possibly lead to toxicity. This information could be a useful adjunct in drug design.
authors.affiliation: Department of Pharmacy, University of California, San Francisco 94143-0446.
authors.forename: L Z
authors.initials: LZ
authors.lastname: Benet
authors.forename: H
authors.initials: H
authors.lastname: Spahn-Langguth
authors.forename: S
authors.initials: S
authors.lastname: Iwakawa
authors.forename: C
authors.initials: C
authors.lastname: Volland
authors.forename: T
authors.initials: T
authors.lastname: Mizuma
authors.forename: S
authors.initials: S
authors.lastname: Mayer
authors.forename: E
authors.initials: E
authors.lastname: Mutschler
authors.forename: E T
authors.initials: ET
authors.lastname: Lin
mesh_terms: D000818:Animals; D002264:Carboxylic Acids / Q000378:metabolism*; D015195:Drug Design; D005965:Glucuronates / Q000097:blood / Q000378:metabolism*; D006801:Humans; D011485:Protein Binding; D013329:Structure-Activity Relationship
chemical_list: D002264:Carboxylic Acids; D005965:Glucuronates