pH-dependent dissolution in vitro and absorption in vivo of weakly basic drugs: development of a canine model.
OBJECTIVE
The aim of this research was to develop a pH-dependent canine absorption model for studying pH effect on both dissolution in vitro and pharmacokinetics in vivo using the weak bases ketoconazole and dipyridamole as model drugs.


METHODS
Ketoconazole and dipyridamole pH-dependent dissolution profiles in vitro were determined by dissolution test at different pH values using USP apparatus II and an Opt-Diss Fiber Optic UV System. In vivo absorption studies for ketoconazole and dipyridamole were performed with crossover design in three groups of beagle dogs under control (no treatment), pentagastrin, and famotidine treatments. Ketoconazole and dipyridamole plasma concentrations were quantified by gradient high performance liquid chromatography mass spectroscopy (HPLC MS/MS). Pharmacokinetic parameters were determined from individual plasma concentration vs. time profiles.


RESULTS
Ketoconazole and dipyridamole displayed pH-dependent dissolution. Increasing the pH of the dissolution medium from 1.2 to 6.8 reduced the extent of dissolution of ketoconazole and dipyridamole at 1 h by 96% and 92%, respectively. In vivo studies in dogs under control (no treatment), pentagastrin, and famotidine treatments show marked differences in systemic ketoconazole and dipyridamole exposure. Area under the concentration-time curve (AUC) increased more than 4-fold as compared to control group, whereas it increased nearly 30-fold for ketoconazole and 9-fold for dipyridamole with pentagastrin (gastric pH approximately 2-3) as compared to famotidine (gastric pH approximately 5-7.5) treatment.


CONCLUSIONS
This work demonstrates a pH-dependent dissolution in vitro and absorption in vivo for the weak bases ketoconazole and dipyridamole independent of food effects. This model is useful to examine pH-dependent effects on oral drug absorption and for screening formulations to overcome the pH dependency.
Zhou
Rong
R
Department of Exploratory Biopharmaceutics & Stability, Pharmaceutical Research Institute, Bristol-Myers Squibb Company, New Brunswick, New Jersey 08903, USA.
Moench
Paul
P
Heran
Christopher
C
Lu
Xujin
X
Mathias
Neil
N
Faria
Teresa N
TN
Wall
Doris A
DA
Hussain
Munir A
MA
Smith
Ronald L
RL
Sun
Duxin
D
D000818:Animals; D004285:Dogs; D005260:Female; D005744:Gastric Acid / Q000502:physiology*; D006863:Hydrogen-Ion Concentration; D007408:Intestinal Absorption / Q000187:drug effects / Q000502:physiology*; D008297:Male; D023421:Models, Animal; D004364:Pharmaceutical Preparations / Q000097:blood / Q000378:metabolism*; D012995:Solubility / Q000187:drug effects
D004364:Pharmaceutical Preparations