Analysis and prediction of absorption behavior of colon-targeted prodrug in rats by GI-transit-absorption model.
The gastrointestinal-transit-absorption (GITA) model is useful for the analysis and the prediction of the absorption behavior of drugs orally administered as solutions. In the present study, we tried to predict the plasma concentration-time profile of a colon-targeted prodrug, salicylazosulfanilic acid (SASA), and its parent drug, 5-aminosalicylic acid (5-ASA) which is regenerated after dosing. Prediction of plasma concentration-time profiles for SASA and 5-ASA was performed based on the GITA model using parameters describing GI-transit kinetics, the absorption in each GI segment, and the regeneration of 5-ASA in cecum. Plasma concentration-time profiles of both SASA and 5-ASA after oral administration of SASA were predicted very well by introducing a factor for the first-pass elimination of 5-ASA into the GITA model. The simulation study using the parameters obtained in the present study showed that about 94.7% of SASA reaches the cecum, where 5-ASA is regenerated very rapidly and 76.0% of 5-ASA is absorbed. Furthermore, the bioavailability of 5-ASA was estimated to be 0.330 because of the first-pass elimination through both cecum and liver. In conclusion, the absorption behaviors of a prodrug and its regenerated parent drug can be predicted very well and be clarified successfully using the GITA model.
Yokoe
Jun-ichi
J
Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Okayama University, 1-1-1 Tsushima-naka, Japan.
Iwasaki
Norio
N
Haruta
Shunji
S
Kadono
Keitaro
K
Ogawara
Ken-ichi
K
Higaki
Kazutaka
K
Kimura
Toshikiro
T
D000818:Animals; D003106:Colon / Q000378:metabolism*; D005544:Forecasting; D005772:Gastrointestinal Transit / Q000502:physiology*; D006801:Humans; D007408:Intestinal Absorption / Q000502:physiology*; D008297:Male; D008954:Models, Biological; D011355:Prodrugs / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar
D011355:Prodrugs