PROBENECID IMPAIRMENT OF ACETAMINOPHEN AND LORAZEPAM CLEARANCE - DIRECT INHIBITION OF ETHER GLUCURONIDE FORMATION

  • 1 January 1985
    • journal article
    • research article
    • Vol. 234  (2) , 345-349
Abstract
Eleven subjects received acetaminophen (650 mg i.v.) on 2 occasions in random sequence, with and without concurrent administration of probenecid (500 mg) every 6 h. Nine subjects similarly received lorazepam (2 mg i.v.) with and without concurrent probenecid. Acetaminophen half-life was prolonged during probenecid treatment (mean .+-. SE, 4.30 .+-. 0.23 vs. 2.51 .+-. 0.16 h; P < 0.001) due to markedly decreased clearance (178 .+-. 13 vs. 329 .+-. 24 ml/min; P < 0.001) with no change in volume of distribution (65 .+-. 4 vs. 69 .+-. 3 l; NS [not significant]). Urinary excretion of acetaminophen glucuronide during 24 h was decreased (84 .+-. 9 vs. 260 .+-. 21 mg of acetaminophen as glucuronide; P < 0.001) and acetaminophen sulfate excretion was increased (323 .+-. 25 vs. 217 .+-. 17 mg of acetaminophen as sulfate; P < 0.005) during concurrent probenecid treatment. The sum of the 2 conjugated metabolites was not significantly different (407 .+-. 28 vs. 476 .+-. 20 mg of acetaminophen as glucuronide plus sulfate excreted per 24 h; NS). Lorazepam half-life was also prolonged during probenecid treatment (33.0 .+-. 3.9 vs. 14.3 .+-. 1.08h; P < 0.001) due to decreased clearance (44.7 .+-. 5.4 vs. 80.3 .+-. 13.2 ml/min; P < 0.001) with no change in volume of distribution (111 .+-. 5 vs. 111 .+-. 7 l; NS). Formation of the ether glucuronides of acetaminophen and lorazepam is impaired markedly by therapeutic doses of probenecid. Sulfate conjugation is not affected. Probenecid may inhibit the clearance of drugs not only due to inhibiton of renal tubular secretion of organic acids, but also by indirect inhibition of ether glucuronide formation.

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