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 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.

• Authors: J L Maggs, B K Park
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 37 Issue 4 Pg. 743-8 (Feb 15 1988) ISSN: 0006-2952 [Print] England
• PMID: 3342105 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Imidazoles
• Imidazolidines
• Serum Albumin
• 2-hydroxysorbinil
• sorbinil

Topics

• Animals
• Imidazoles (metabolism)
• Imidazolidines
• In Vitro Techniques
• Male
• Microsomes, Liver (metabolism)
• Protein Binding
• Rats
• Rats, Inbred Strains
• Serum Albumin (metabolism)