Abstract
Acyl glucuronides of drugs and bilirubin have been shown in the past decade to be reactive metabolites undergoing acyl migration and irreversible binding. The latter reaction has been hypothesized to be facilitated by or to proceed through the formation of a reversible complex. Furthermore, it has been suggested that the decreased binding seen in patients with compromised excretory function may be due to competition by elevated plasma concentrations of the glucuronides. In these reversible binding studies, we characterized the extent and the “site” of binding of tolmetin, zomepirac, their glucuronides and isomeric conjugates. We also examined the displacement between the parent drugs and their glucuronide conjugates using a rapid ultrafiltration method. Tolmetin exhibited three classes of binding sites with a primary association constant of 1.7×106 M−1 (Kdl=0.60 μM). The primary association constant of zomepirac (1.16×106 M−1, Kdl=0.86 μM) is similar to that of tolmetin. The β 1 and α/β3 glucuronides of both compounds bind to a lesser extent than their parent aglycones. The isomeric glucuronide conjugates of both compounds showed much stronger binding than the β/1 conjugates. Of the four glucuronides investigated, tolmetin glucuronide-α/β3 isomer was bound by fatty acid free human serum albumin with the highest affinity (4.6×105 M−1, Kd=2.22 μM). Protein binding of the parent drugs and conjugates were decreased significantly at pH 5.0. In displacement studies, except for salicylate and acetylsalicylate, drugs known to bind to Sites I and II as well as the digitoxin and tamoxifen binding sites had little inhibitory effect on the binding of tolmetin, zomepirac, and their glucuronide conjugates.
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Supported in part by Grant GM 36633 from the National Institute of General Medical Sciences.
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Ojingwa, J.C., Spahn-Langguth, H. & Benet, L.Z. Reversible binding of tolmetin, zomepirac, and their glucuronide conjugates to human serum albumin and plasma. Journal of Pharmacokinetics and Biopharmaceutics 22, 19–40 (1994). https://doi.org/10.1007/BF02353408
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DOI: https://doi.org/10.1007/BF02353408