Pharmaceutical Research

, Volume 7, Issue 1, pp 21–27

Irreversible Binding of Tolmetin Glucuronic Acid Esters to Albumin in Vitro

  • Alain Munafo
  • Antony F. McDonagh
  • Philip C. Smith
  • Leslie Z. Benet
Article

DOI: 10.1023/A:1015823206607

Cite this article as:
Munafo, A., McDonagh, A.F., Smith, P.C. et al. Pharm Res (1990) 7: 21. doi:10.1023/A:1015823206607

Abstract

Tolmetin glucuronide (TG), extracted and purified from human urine, was incubated with albumin in vitro. The degradation profile and irreversible binding to protein were investigated and kinetic parameters calculated. Standard conditions were as follows: TG, 30 µg/ml; human serum albumin (HSA), 3%; pH 7.45; 37°C. Lower pH enhanced TG stability and reduced both the extent and the rate of irreversible binding. HSA also increased TG stability, compared to protein-free buffer, but the opposite was observed with bovine serum albumin (BSA). With BSA, irreversible binding was much less, but the rate of adduct formation was the same as with HSA. Essentially fatty acid free HSA behaved similarly to HSA. Preincubation of HSA with warfarin, or diazepam, or an excess of tolmetin, did not influence irreversible binding significantly. In buffer, acyl migration led predominantly to one isomer. This isomer bound irreversibly to HSA, although more slowly and to a lesser extent than the β1-isomer. Incubation of TG with poly-L-lysine also resulted in irreversible binding but to a lesser extent than with HSA. Our results suggest that there is more than one binding mechanism, with the preferential pathway a function of the isomers present and the experimental conditions.

tolmetin irreversible binding acyl glucuronide acyl migration serum albumin 

Copyright information

© Plenum Publishing Corporation 1990

Authors and Affiliations

  • Alain Munafo
    • 1
  • Antony F. McDonagh
    • 3
  • Philip C. Smith
    • 1
    • 3
  • Leslie Z. Benet
    • 1
  1. 1.Department of Pharmacy, School of PharmacyUniversity of CaliforniaSan Francisco
  2. 2.Division of Clinical Pharmacology, Department of Internal MedicineCentre Hospitalier Universitaire VaudoisLausanneSwitzerland
  3. 3.Liver Center, School of MedicineUniversity of CaliforniaSan Francisco
  4. 4.College of Pharmacy, PHR 4.214EThe University of Texas at AustinAustin