Drug-protein conjugates—XVI: Studies of sorbinil metabolism: Formation of 2-hydroxysorbinil and unstable protein conjugates

Abstract

The metabolism of sorbinil ((+)6-fluoro-spiro (chroman-4, 4′-imidazolidine)-2′,5′ dione), an aldose reductase inhibitor associated with immunological adverse reactions, was studied in vivo and in vitro with particular reference to the formation of protein conjugates of 2-hydroxysorbinil and their further metabolism. [8- 3H]Sorbinil was rapidly and extensively metabolized in the rat. 2-Hydroxysorbinil (2HSB) and a phenolic primary alcohol (2,4-imidazolidinedione 5-(2-hydroxyethyl)-5-(5-fluoro-2-hydroxyphenyl); IHFH) were its principal urinary metabolites; over 0–24 hr, they represented 17.0 ± 0.7% (mean ± SD, N = 4) and 7.1 ± 0.7% of the dose, respectively. [ 3H]2HSB isolated from urine and re-administered was converted to IHFH. Chronic dosing with sorbinil (150 mg/kg × 5) induced 2-hydroxylation of the drug, the 0–24 hr urinary excretion of 2HSB increasing from 17.0 ± 0.7% to 24.7 ± 3.4% of the dose (P < 0.05 by Students' paired t-test). The biotransformation of 2HSB to IHFH was rationalized in terms of an open-chain aldehyde intermediate. Since aldehydes form both stable and unstable protein adducts, 2HSB was potentially a pro-reactive metabolite and initiator of the hypersensitivity reaction associated with sorbinil. However, [ 3H]2HSB was neither metabolized by human liver microsomes nor underwent irreversible binding to the microsomal protein. Nevertheless, the mild reductant sodium cyanoborohydride, although without effect on microsomal binding of [ 3H]2HSB, enhanced binding to human serum albumin. Formation of unstable Schiff base adducts was indicated.