title: Screening of the inhibitory effect of xenobiotics on alcohol metabolism using S9 rat liver fractions.
abstract: The purpose of this work was to develop and optimize a simple and suitable method to detect the potential inhibitory effect of drugs and medicines on alcohol dehydrogenase (ADH) activity in order to evaluate the possible interactions between medicines and alcohol metabolism. Commonly used medicines that are often involved in court litigations related with driving under the influence of alcohol were selected. Alprazolam, flunitrazepam and tramadol were tested as drugs with no known effect on ADH activity. Cimetidine, reported previously as having inhibitory effect on ADH, and 4-methylpyrazole (4-MP), a well known ADH inhibitor, were tested as positive controls. Apart from 4-MP, tramadol was identified as having the higher inhibitory effect with an IC50 of 44.7 × 10(-3)mM, followed by cimetidine (IC50 of 122.9 × 10(-3)mM). Alprazolam and flunitrazepam also reduced liver ADH activity but to a smaller extent (inhibition of 11.8 ± 5.0% for alprazolam 1.0mM and 34.5 ± 7.1% for flunitrazepam 0.04 mM). Apart from cimetidine, this is the first report describing the inhibitory effect of these drugs on ethanol metabolism. The results also show the suitability of the method to screen for inhibitory effect of drugs on ethanol metabolism helping to identify drugs for which further study is justified.
authors: i-Med.UL, Faculdade de Farmácia, Universidade de Lisboa, Av. Prof Gama Pinto, 1649-003 Lisboa, Portugal.
authors: Catarina
authors: C
authors: Dias
authors: Bernard
authors: B
authors: Testa
authors: Graça
authors: G
authors: Soveral
authors: Mário
authors: M
authors: Dias
authors: Luís
authors: L
authors: Constantino
mesh_terms: D000426:Alcohol Dehydrogenase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000525:Alprazolam / Q000494:pharmacology; D000818:Animals; D002927:Cimetidine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D000431:Ethanol / Q000378:metabolism / Q000493:pharmacokinetics*; D005445:Flunitrazepam / Q000494:pharmacology; D000077604:Fomepizole; D020128:Inhibitory Concentration 50; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D000091243:Ribosomal Protein S9; D012269:Ribosomal Proteins / Q000187:drug effects* / Q000378:metabolism; D014147:Tramadol / Q000494:pharmacology; D015262:Xenobiotics / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D011720:Pyrazoles; D000091243:Ribosomal Protein S9; D012269:Ribosomal Proteins; D015262:Xenobiotics; D014147:Tramadol; D000431:Ethanol; D005445:Flunitrazepam; D002927:Cimetidine; D000077604:Fomepizole; D000426:Alcohol Dehydrogenase; D000525:Alprazolam