title: Investigation of some factors contributing to negative food effects.
abstract: A drug is defined as exhibiting negative food effects, if the co-administration of food statistically decreases its area under the curve, AUC, when compared with its administration on a fasted stomach. In this study, the role of biopharmaceutical factors that contribute to negative food effects was studied using furosemide, nadolol, tacrine and atenolol (as model compounds exhibiting negative food effects), and prednisolone, hydrochlorothiazide and ibuprofen (as model compounds that do not show any food effects). The physiological pH of the upper intestinal tract is lower, at pH 5, in the postprandial state when compared with the preprandial state, pH 6.5. Drugs that exhibited negative food effects had low apical to basolateral Caco-2 permeabilities, low pKa/pKb and Log P values of less than 1. The drugs exhibiting negative food effects had low distribution coefficients at the pH conditions of the fed and fasted states. Furosemide, being a hydrophilic, poorly soluble acidic drug showed lower solubility in the fed state when compared with the fasted state. Basic drugs, atenolol, nadolol and tacrine, are ionized to a higher extent in the fed state and exhibit lower permeability and lower absorption when compared with the fasted state. Thus, drugs were found to exhibit negative food effects owing to their decrease in solubility or permeability in the upper intestinal tract of the fed state when compared with the fasted state.
authors.affiliation: Department of Pharmaceutics and Medicinal Chemistry, TJ Long School of Pharmacy and Health Sciences, University of the Pacific, Stockton, CA 95211, USA.
authors.forename: Venugopal P
authors.initials: VP
authors.lastname: Marasanapalle
authors.forename: John R
authors.initials: JR
authors.lastname: Crison
authors.forename: Jingwen
authors.initials: J
authors.lastname: Ma
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Li
authors.forename: Bhaskara R
authors.initials: BR
authors.lastname: Jasti
mesh_terms: D000818:Animals; D019540:Area Under Curve; D018938:Caco-2 Cells; D005215:Fasting; D005260:Female; D018565:Food-Drug Interactions; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007408:Intestinal Absorption; D008297:Male; D010539:Permeability; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D019518:Postprandial Period / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D012995:Solubility
chemical_list: D004364:Pharmaceutical Preparations