title: Concomitant intake of alcohol may increase the absorption of poorly soluble drugs.
abstract: Ethanol can increase the solubility of poorly soluble and hence present a higher drug concentration in the gastrointestinal tract. This may produce a faster and more effective absorption resulting in variable and/or high drug plasma concentrations, both of which can lead to adverse drug reactions. In this work we therefore studied the solubility and absorption effects of nine diverse compounds when ethanol was present. The apparent solubility was measured using the μDiss Profiler Plus (pION, MA) in four media representing gastric conditions with and without ethanol. The solubility results were combined with in-house data on solubility in intestinal fluids (with and without ethanol) and pharmacokinetic parameters extracted from the literature and used as input in compartmental absorption simulations using the software GI-Sim. Apparent solubility increased more than 7-fold for non-ionized compounds in simulated gastric fluid containing 20% ethanol. Compounds with weak base functions (cinnarizine, dipyridamole and terfenadine) were completely ionized at the studied gastric pH and their solubility was therefore unaffected by ethanol. Compounds with low solubility in intestinal media and a pronounced solubility increase due to ethanol in the upper gastric compartments showed an increased absorption in the simulations. The rate of absorption of the acidic compounds indomethacin and indoprofen was slightly increased but the extent of absorption was unaffected as the complete doses were readily absorbed even without ethanol. This was likely due to a high apparent solubility in the intestinal compartment where the weak acids are ionized. The absorption of the studied non-ionizable compounds increased when ethanol was present in the gastric and intestinal media. These results indicate that concomitant intake of alcohol may significantly increase the solubility and hence, the plasma concentration for non-ionizable, lipophilic compounds with the potential of adverse drug reactions to occur.
authors.affiliation: Department of Pharmacy, Uppsala Biomedical Center, Uppsala University, P.O. Box 580, SE-751 23 Uppsala, Sweden.
authors.forename: Jonas H
authors.initials: JH
authors.lastname: Fagerberg
authors.affiliation: Department of Pharmacy, Uppsala Biomedical Center, Uppsala University, P.O. Box 580, SE-751 23 Uppsala, Sweden.
authors.forename: Erik
authors.initials: E
authors.lastname: Sjögren
authors.affiliation: Department of Pharmacy, Uppsala Biomedical Center, Uppsala University, P.O. Box 580, SE-751 23 Uppsala, Sweden. Electronic address: christel.bergstrom@farmaci.uu.se.
authors.forename: Christel A S
authors.initials: CAS
authors.lastname: Bergström
mesh_terms: D003198:Computer Simulation; D004347:Drug Interactions; D000431:Ethanol / Q000008:administration & dosage / Q000737:chemistry*; D005750:Gastric Juice / Q000737:chemistry; D065569:Gastrointestinal Absorption; D041981:Gastrointestinal Tract / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D008954:Models, Biological; D004364:Pharmaceutical Preparations / Q000008:administration & dosage / Q000737:chemistry*; D010599:Pharmacokinetics; D012995:Solubility
chemical_list: D004364:Pharmaceutical Preparations; D000431:Ethanol
keywords: Absorption modeling; Biorelevant dissolution; Cinnarizine (PubChem CID: 1547484); Dipyridamole (PubChem CID: 3108); Ethanol; Felodipine (PubChem CID: 3333); Griseofulvin (PubChem CID: 441140); Indomethacin (PubChem CID: 3715); Indoprofen (PubChem CID: 3718); Molecular properties; Poorly soluble compounds; Progesterone (PubChem CID: 5994); Solubility; Terfenadine (PubChem CID: 5405); Tolfenamic acid (PubChem CID: 610479)