Estimation of intragastric solubility of drugs: in what medium?
OBJECTIVE
To measure the solubility of four drugs in human gastric aspirates, canine gastric aspirates (CGF) and simulated gastric fluids in order to propose a medium for estimating intragastric drug solubility relevant to a bioavailability study in the fasted state.


METHODS
Intragastric environment after administration of water to healthy fasted adults and to healthy fasted dogs (this study) was initially characterized. Solubilities were then measured with the shake-flask method in gastric fluid aspirated after the administration of water to healthy fasted adults and to healthy fasted dogs, in various simulated gastric fluids, i.e. SGF(SLS), SGF(Triton), FaSSGF, FaSSGF(NaCl), and in various HCl solutions with pH values ranging from 1.2 to 2.9.


RESULTS
In all cases, FaSSGF performed better than canine aspirates, SGF(SLS), SGF(Triton), or FaSSGF(NaCl) in predicting solubility in HGF. However, its superiority over HCl pH 1.6 was not clear. For ketoconazole, dipyridamole, miconazole, and felodipine deviations of solubility data in FaSSGF from solubility data in HGF were non-significant, 34, -39 and 252%, respectively, whereas the corresponding deviations of data in HCl pH 1.6 from data in HGF were non-significant, 24, 70, and 130%, respectively.


CONCLUSIONS
Combining data in FaSSGF and HCl pH 1.6 is comparatively the most efficient way to get an estimate of drug solubility in the fasting gastric contents during a bioavailability study. However, accurate estimation of intragastric solubility is limited by the changing environment during intragastric residence of solid particles and the degree of simulation of intragastric composition.
Vertzoni
Maria
M
Faculty of Pharmacy, Laboratory of Biopharmaceutics and Pharmacokinetics, University of Athens, Panepistimiopolis, 157 71, Zografou, Greece.
Pastelli
Eleni
E
Psachoulias
Dimitris
D
Kalantzi
Lida
L
Reppas
Christos
C
D000328:Adult; D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D004176:Dipyridamole / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D004285:Dogs; D005215:Fasting; D015736:Felodipine / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D005260:Female; D005750:Gastric Juice / Q000737:chemistry*; D005753:Gastric Mucosa / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007654:Ketoconazole / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D007700:Kinetics; D008825:Miconazole / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D009994:Osmolar Concentration; D004364:Pharmaceutical Preparations / Q000008:administration & dosage / Q000737:chemistry* / Q000378:metabolism; D011092:Polyethylene Glycols / Q000737:chemistry; D012995:Solubility; D012996:Solutions / Q000737:chemistry; D013270:Stomach / Q000737:chemistry; D013997:Time Factors; D014867:Water / Q000008:administration & dosage
D000935:Antifungal Agents; D004364:Pharmaceutical Preparations; D012996:Solutions; D014867:Water; D011092:Polyethylene Glycols; D004176:Dipyridamole; D008825:Miconazole; D015736:Felodipine; D007654:Ketoconazole