Drug-protein conjugates--XVI. Studies of sorbinil metabolism: formation of 2-hydroxysorbinil and unstable protein conjugates.
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 x 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 less than 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.
Maggs
J L
JL
Department of Pharmacology and Therapeutics, University of Liverpool, U.K.
Park
B K
BK
D000818:Animals; D007093:Imidazoles / Q000378:metabolism*; D048289:Imidazolidines; D066298:In Vitro Techniques; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D011485:Protein Binding; D051381:Rats; D011919:Rats, Inbred Strains; D012709:Serum Albumin / Q000378:metabolism*
D007093:Imidazoles; D048289:Imidazolidines; D012709:Serum Albumin; C054924:2-hydroxysorbinil; C026411:sorbinil