Inhibition of acetaminophen and lorazepam glucuronidation in vitro by probenecid.
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.
von Moltke
L L
LL
Division of Clinical Pharmacology, Tufts University School of Medicine, Boston, Massachusetts 02111.
Manis
M
M
Harmatz
J S
JS
Poorman
R
R
Greenblatt
D J
DJ
D000082:Acetaminophen / Q000031:analogs & derivatives / Q000378:metabolism*; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D004347:Drug Interactions; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008140:Lorazepam / Q000031:analogs & derivatives / Q000378:metabolism*; D008251:Macaca; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008862:Microsomes, Liver / Q000187:drug effects; D011339:Probenecid / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D000082:Acetaminophen; C037386:acetaminophen glucuronide; D008140:Lorazepam; C031290:lorazepam glucuronide; D011339:Probenecid