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Irreversible protein binding of [14C]-practolol metabolite(s) to hamster liver microsomes (proceedings).

The toxic effects of some chemically stable drugs, e.g. paracetamol, phenacetin and isoniazid, correlate with their metabolism by the microsomal mixed function oxidases via transient reactive intermediates which bind irreversibly to tissue proteins (Gillette, Mitchell & Brodie, 1974). Practolol is a cardioselective f-blocking drug which can give rise, in a small proportion of patients, to characteristic skin and eye lesions and sclerosing peritonitis (Waal-Manning, 1975). As some mechanistic hypotheses have involved an immunological reaction (Amos, Brigden & McKerron, 1975; Behan, Behan, Zacharias & Nicholls, 1976), we have investigated the reactivity of practolol and its metabolites with tissue and serum proteins in order to evaluate its potential to form a possible antigenic complex. [14C]-practolol (nuclear labelled) was incubated in air with hamster liver microsomes in the presence of NADPH. The irreversible binding of reactive [14CIintermediates to microsomal proteins was determined by liquid scintillation counting after exhaustive solvent extraction of the microsomes (Potter, Davis, Mitchell,