title: Effect of coadministered drugs and ethanol on the binding of therapeutic drugs to human serum in vitro.
abstract: The effects of coadministered drugs and ethanol on the binding of therapeutic drugs to human serum in vitro was investigated. Acetaminophen, lidocaine, phenobarbital, quinidine, theophylline, and valproic acid were added to pooled human serum at therapeutic concentrations. To each preparation was added one additional drug at three concentrations ranging from therapeutic to toxic. The following eight target drug/added drug combinations were studied: acetaminophen/phenobarbital. acetaminophen/theophylline, lidocaine/quinidine, phenobarbital/acetaminophen, phenobarbital/valproic acid, quinidine/lidocaine, theophylline/acetaminophen, and valproic acid/phenobarbital. Each serum without the other added drug as well as the serum supplemented with the other drug at the three concentrations was dialyzed against phosphate buffer. Similarly dialyzed were phenobarbital, quinidine, and theophylline, both alone at therapeutic concentrations in serum and with ethanol at three different concentrations in serum. The percentage of drug binding in each preparation was calculated. Acetaminophen diminished the binding of theophylline to human serum by a net change of 5.7% (percentage increase in free drug fraction [FDF], 11.0%) at 662 micromol/L and by a net change of 7.1% (percentage increase in FDF, 13.7%) at 1324 micromol/L. Theophylline decreased the binding of acetaminophen by a net change of 6.8% (percentage increase in FDF, 8.8%) at 277.5 micromol/L; phenobarbital reduced it by a net change of 6.6% (percentage increase in FDF, 8.5%) at 431 micromol/L. Valproic acid diminished binding of phenobarbital by a net change of 9.9% (percentage increase in FDF, 21.2%) at 1732 micromol/L. No significant effects were noted with other drug combinations or with the addition of ethanol. Coingestion of acetaminophen with theophylline, phenobarbital with acetaminophen, and valproic acid with phenobarbital at high to toxic concentrations decreases the binding of the target drug. The resulting increase in free drug concentration may lead to enhanced drug effect in vivo.
authors.affiliation: Department of Pathology, University of California, San Diego Medical Center, 92103-8320, USA.
authors.forename: D N
authors.initials: DN
authors.lastname: Bailey
mesh_terms: D001798:Blood Proteins / Q000378:metabolism; D002492:Central Nervous System Depressants / Q000494:pharmacology*; D003956:Dialysis; D004347:Drug Interactions; D016903:Drug Monitoring; D000431:Ethanol / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D011485:Protein Binding
chemical_list: D001798:Blood Proteins; D002492:Central Nervous System Depressants; D004364:Pharmaceutical Preparations; D000431:Ethanol