title: Utilization of Gastrointestinal Simulator, an in Vivo Predictive Dissolution Methodology, Coupled with Computational Approach To Forecast Oral Absorption of Dipyridamole.
abstract: Weakly basic drugs exhibit a pH-dependent dissolution profile in the gastrointestinal (GI) tract, which makes it difficult to predict their oral absorption profile. The aim of this study was to investigate the utility of the gastrointestinal simulator (GIS), a novel in vivo predictive dissolution (iPD) methodology, in predicting the in vivo behavior of the weakly basic drug dipyridamole when coupled with in silico analysis. The GIS is a multicompartmental dissolution apparatus, which represents physiological gastric emptying in the fasted state. Kinetic parameters for drug dissolution and precipitation were optimized by fitting a curve to the dissolved drug amount-time profiles in the United States Pharmacopeia apparatus II and GIS. Optimized parameters were incorporated into mathematical equations to describe the mass transport kinetics of dipyridamole in the GI tract. By using this in silico model, intraluminal drug concentration-time profile was simulated. The predicted profile of dipyridamole in the duodenal compartment adequately captured observed data. In addition, the plasma concentration-time profile was also predicted using pharmacokinetic parameters following intravenous administration. On the basis of the comparison with observed data, the in silico approach coupled with the GIS successfully predicted in vivo pharmacokinetic profiles. Although further investigations are still required to generalize, these results indicated that incorporating GIS data into mathematical equations improves the predictability of in vivo behavior of weakly basic drugs like dipyridamole.
authors.affiliation: College of Pharmacy, University of Michigan , 428 Church Street, Ann Arbor, Michigan 48109-1065, United States.|Drug Metabolism and Pharmacokinetics, Research Center, Mochida Pharmaceutical Company Limited , 722 Uenohara, Jimba, Gotemba, Shizuoka 412-8524, Japan.
authors.forename: Kazuki
authors.identifier: 0000-0001-6259-2089
authors.initials: K
authors.lastname: Matsui
authors.affiliation: College of Pharmacy, University of Michigan , 428 Church Street, Ann Arbor, Michigan 48109-1065, United States.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Tsume
authors.affiliation: Pharmacokinetics Group, Sawai Pharmaceutical Company Limited , 5-2-30, Miyahara, Yodogawa-ku, Osaka 532-0003, Japan.
authors.forename: Susumu
authors.initials: S
authors.lastname: Takeuchi
authors.affiliation: College of Pharmacy, University of Michigan , 428 Church Street, Ann Arbor, Michigan 48109-1065, United States.
authors.forename: Amanda
authors.initials: A
authors.lastname: Searls
authors.affiliation: College of Pharmacy, University of Michigan , 428 Church Street, Ann Arbor, Michigan 48109-1065, United States.
authors.forename: Gordon L
authors.identifier: 0000-0003-0355-911X
authors.initials: GL
authors.lastname: Amidon
mesh_terms: D061605:Administration, Intravenous / Q000379:methods; D000284:Administration, Oral; D000368:Aged; D004176:Dipyridamole / Q000493:pharmacokinetics*; D005260:Female; D005746:Gastric Emptying / Q000502:physiology; D041981:Gastrointestinal Tract / Q000378:metabolism*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007408:Intestinal Absorption / Q000502:physiology; D007700:Kinetics; D008297:Male; D008954:Models, Biological; D012995:Solubility
chemical_list: D004176:Dipyridamole
keywords: GIS; dipyridamole; in silico; in vivo predictive dissolution; intestinal absorption; modeling and simulation; precipitation; supersaturation