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Inhibition of acetaminophen and lorazepam glucuronidation in vitro by probenecid
Author(s) -
Von Moltke Lisa L.,
Manis Melanie,
Harmatz Jerold S.,
Poorman Roger,
Greenblatt David J.
Publication year - 1993
Publication title -
biopharmaceutics and drug disposition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.419
H-Index - 58
eISSN - 1099-081X
pISSN - 0142-2782
DOI - 10.1002/bdd.2510140204
Subject(s) - glucuronidation , probenecid , lorazepam , microsome , acetaminophen , chemistry , in vivo , pharmacology , in vitro , microsoma , non competitive inhibition , glucuronide , biochemistry , metabolism , enzyme , biology , anesthesia , medicine , microbiology and biotechnology
The effect of probenecid on glucuronidation of acetaminophen and lorazepam in hepatic microsomes from various species was studied to see if in vitro results were consistent with previous in vivo observations. Mouse, rat, and human microsomes were incubated with acetaminophen and probenecid while monkey microsomes were incubated with lorazepam and probenecid. Glucuronidation rates in all species varied with substrate, protein, and detergent concentrations. Mice exhibited faster rates of glucuronidation than rats or humans. All species showed inhibition of glucuronidation of acetaminophen or lorazepam when probenecid was added. Analysis suggested competitive inhibition. Thus, in vitro studies support in vivo results and confirm that the inhibition takes place at the hepatic level.