title: In vitro analysis of the interaction between sucralfate and ketoconazole.
abstract: In healthy volunteers, the bioavailability of ketoconazole is significantly decreased during simultaneous administration with sucralfate. In an effort to address this problem, we examined the interaction between sucralfate and ketoconazole in aqueous solutions and in simulated gastric fluid (SGF) at various initial pHs (1, 2, 3, and 6) in the presence or absence of glutamic acid hydrochloride (GA). Samples from each solution were taken 30 min and 2 h after the addition of ketoconazole to evaluate the solubility of ketoconazole over the usual time period of maximal absorption of ketoconazole in humans. The addition of GA to SGF leads to an increase in solution acidity, while the pHs of SGF at a pH of 1, 2, or 3 are markedly increased by the addition of sucralfate. There is a net decrease in acidity from initial pHs for the pH 1, 2, and 3 solutions when GA and sucralfate are combined. The concentration of ketoconazole in SGF at pHs of 1, 2, 3, 4, and 6 was evaluated in order to assess the pH-dependent solubility properties of the drug in the absence of other interacting species. Regardless of the initial pH, combinations of GA plus ketoconazole showed high concentrations of ketoconazole (approximately 100%) in solution. In contrast, significant decreases in the concentration of soluble ketoconazole were observed when sucralfate was mixed with ketoconazole, and, in some cases, soluble ketoconazole was not detectable. The addition of GA to a mixture of sucralfate and ketoconazole leads to a significant increase in the concentration of solubilized ketoconazole. Nonetheless, important sucralfate-ketoconazole interactions are still observed. After 2 h, approximately 35% of the maximal ketoconazole concentration remained in solution. Comparison of the ketoconazole concentrations at different pHs with the predicted concentrations of the three protonation species of ketoconazole [H2(ketoconazole)(2+), H(ketoconazole)(+), or ketoconazole] showed no correlation. Therefore, the decrease in ketoconazole solubility is not simply a reflection of pH perturbation associated with the dissolution of sucralfate. The observed data are most consistent with a model that has H2(ketoconazole)(2+) or H(ketoconazole)(+) forming an electrostatic interaction with the sucralfate polyanion. The findings of this study suggest that the coadministration of sucralfate with other azole antifungal agents should be investigated.
authors.affiliation: Department of Chemistry, University of Michigan, Ann Arbor 48109-1065, USA.
authors.forename: J D
authors.initials: JD
authors.lastname: Hoeschele
authors.forename: A K
authors.initials: AK
authors.lastname: Roy
authors.forename: V L
authors.initials: VL
authors.lastname: Pecoraro
authors.forename: P L
authors.initials: PL
authors.lastname: Carver
mesh_terms: D002626:Chemistry, Pharmaceutical; D004347:Drug Interactions; D005750:Gastric Juice / Q000187:drug effects / Q000378:metabolism; D005971:Glutamates / Q000494:pharmacology*; D018698:Glutamic Acid; D006863:Hydrogen-Ion Concentration; D007654:Ketoconazole / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D007700:Kinetics; D008954:Models, Biological; D018377:Neurotransmitter Agents / Q000494:pharmacology; D012995:Solubility; D013392:Sucralfate / Q000494:pharmacology*; D014867:Water / Q000737:chemistry
chemical_list: D005971:Glutamates; D018377:Neurotransmitter Agents; D014867:Water; D018698:Glutamic Acid; D013392:Sucralfate; D007654:Ketoconazole