Predicting human intestinal permeability using single-pass intestinal perfusion in rat.
OBJECTIVE
The aim of the study was the prediction of human intestinal permeability and fraction absorbed of oral dose using single-pass intestinal perfusion technique (SPIP) in rats.


METHODS
Permeability coefficients in anaesthetized rats were determined for 14 compounds. Drug solution in phosphate buffered saline (PBS) was perfused through a ingle-pass intestinal perfusion (SPIP) with flow rate of 0.21 ml/min and samples were taken from outlet tubing at different time points up to 90 min. Phenol red was used as a non-absorbable marker to correct water flux through the segment. Drug concentrations in samples were determined using HPLC and permeability coefficients (Peff) were calculated.


RESULTS
The examined compounds demonstrated approximately 12.5 fold difference in magnitude for rat permeability coefficients among themselves. These values were compared with published data for human intestinal permeability, and a strong correlation was found between Peff (rat) and Peff (human); (Peff (human) = 11.04 Peff (rat) - 0.0003; R2= 0.93, P<0.0001). Subsequently the fraction dose absorbed in human (Fa) was estimated and predicted after oral dosing considering Fa(human)=1-e - 38450Peff(rat) (R2= 0.91, P<0.0001).


CONCLUSIONS
Considering the high correlation of rat Peff values with those of human we conclude that the SPIP could be utilized with precision to predict the human intestinal permeability. It may also be used as a reliable technique to predict the fraction of dose absorbed following oral administration of drug in solution or regular release dosage form in human.
Zakeri-Milani
Parvin
P
Department of Pharmaceutics, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran.
Valizadeh
Hadi
H
Tajerzadeh
Hosnieh
H
Azarmi
Yadollah
Y
Islambolchilar
Ziba
Z
Barzegar
Saeed
S
Barzegar-Jalali
Mohammad
M
D000284:Administration, Oral; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D004355:Drug Stability; D005544:Forecasting; D006801:Humans; D007408:Intestinal Absorption; D007583:Jejunum / Q000378:metabolism; D008297:Male; D008970:Molecular Weight; D010477:Perfusion / Q000379:methods; D010539:Permeability; D010599:Pharmacokinetics; D010637:Phenolsulfonphthalein; D051381:Rats; D017208:Rats, Wistar; D015203:Reproducibility of Results; D013045:Species Specificity
D010637:Phenolsulfonphthalein