Rate-limiting steps of oral absorption for poorly water-soluble drugs in dogs; prediction from a miniscale dissolution test and a physiologically-based computer simulation.
OBJECTIVE
Nonlinear oral absorption due to poor solubility often impedes drug development. The purpose of this study was to elucidate the rate-limiting process in oral absorption of Biopharmaceutical Classification System (BCS) class II (low solubility-high permeability) drugs in order to predict nonlinear absorption of dose caused by solubility-limited absorption.


METHODS
Oral absorption of danazol, griseofulvin, and aprepitant was predicted from a miniscale dissolution test and a physiologically-based model. The effect of particle size reduction and dose increase on absorption was investigated in vitro and in vivo to clarify the rate-limiting steps of dissolution-rate-limited and solubility-limited absorption.


RESULTS
The rate-limiting steps of oral absorption were simulated and increase in the dissolution rate and administration dose showed a shift from dissolution rate-limited to solubility-limited absorption. In the study in dogs, particle size reduction improved the oral absorption of large particle drugs but had little effect on small particle drugs. Dose nonlinearity was observed with small particles at a high dose. Our model quantitatively predicted results observed in vivo, including but not exclusively, dissolution-rate-limited and solubility-limited absorption.


CONCLUSIONS
The present study provides a powerful tool to predict dose nonlinearity and will aid in the success of BCS class II drug development.
Discovery Platform Technology Department, Chugai Pharmaceutical Co., Ltd., 1-135 Komakado, Gotemba, Shizuoka, 412-8513, Japan, takanorus@chugai-pharm.co.jp
Ryusuke
R
Takano
Kentaro
K
Furumoto
Koji
K
Shiraki
Noriyuki
N
Takata
Yoshiki
Y
Hayashi
Yoshinori
Y
Aso
Shinji
S
Yamashita
D000284:Administration, Oral; D000818:Animals; D000077608:Aprepitant; D003198:Computer Simulation; D003613:Danazol / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D004285:Dogs; D006118:Griseofulvin / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D007408:Intestinal Absorption; D008954:Models, Biological; D009025:Morpholines / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D017711:Nonlinear Dynamics; D010316:Particle Size; D010539:Permeability; D015203:Reproducibility of Results; D012995:Solubility; D013678:Technology, Pharmaceutical / Q000379:methods*; D014867:Water / Q000737:chemistry*
D009025:Morpholines; D014867:Water; D000077608:Aprepitant; D006118:Griseofulvin; D003613:Danazol