An in vitro methodology for forecasting luminal concentrations and precipitation of highly permeable lipophilic weak bases in the fasted upper small intestine.
OBJECTIVE
To develop an in vitro methodology for prediction of concentrations and potential precipitation of highly permeable, lipophilic weak bases in fasted upper small intestine based on ketoconazole and dipyridamole luminal data. Evaluate usefulness of methodology in predicting luminal precipitation of AZD0865 and SB705498 based on plasma data.


METHODS
A three-compartment in vitro setup was used. Depending on the dosage form administered in in vivo studies, a solution or a suspension was placed in the gastric compartment. A medium simulating the luminal environment (FaSSIF-V2plus) was initially placed in the duodenal compartment. Concentrated FaSSIF-V2plus was placed in the reservoir compartment.


RESULTS
In vitro ketoconazole and dipyridamole concentrations and precipitated fractions adequately reflected luminal data. Unlike luminal precipitates, in vitro ketoconazole precipitates were crystalline. In vitro AZD0865 data confirmed previously published human pharmacokinetic data suggesting that absorption rates are not affected by luminal precipitation. In vitro SB705498 data predicted that significant luminal precipitation occurs after a 100 mg or 400 mg but not after a 10 mg dose, consistent with human pharmacokinetic data.


CONCLUSIONS
An in vitro methodology for predicting concentrations and potential precipitation in fasted upper small intestine, after administration of highly permeable, lipophilic weak bases in fasted upper small intestine was developed and evaluated for its predictability in regard to luminal precipitation.
Department of Pharmaceutical Technology, National & Kapodistrian University of Athens, Athens, Greece.
Dimitrios
D
Psachoulias
Maria
M
Vertzoni
James
J
Butler
David
D
Busby
Moira
M
Symillides
Jennifer
J
Dressman
Christos
C
Reppas
D000935:Antifungal Agents / Q000737:chemistry / Q000378:metabolism*; D004176:Dipyridamole / Q000737:chemistry / Q000378:metabolism*; D005215:Fasting; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000378:metabolism*; D007408:Intestinal Absorption; D007421:Intestine, Small / Q000378:metabolism*; D007654:Ketoconazole / Q000737:chemistry / Q000378:metabolism*; D008954:Models, Biological; D010539:Permeability; D010975:Platelet Aggregation Inhibitors / Q000737:chemistry / Q000378:metabolism*; D011725:Pyridines / Q000737:chemistry / Q000378:metabolism*; D011759:Pyrrolidines / Q000737:chemistry / Q000378:metabolism*; D012995:Solubility; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors; D014508:Urea / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism
C514958:AZD0865; D000935:Antifungal Agents; D007093:Imidazoles; D010975:Platelet Aggregation Inhibitors; D011725:Pyridines; D011759:Pyrrolidines; C512301:SB 705498; D050916:TRPV Cation Channels; D004176:Dipyridamole; D014508:Urea; D007654:Ketoconazole