Oral absorption of cephalosporins is quantitatively predicted from in vitro uptake into intestinal brush border membrane vesicles.
In order to establish a method to predict oral absorption of drugs, which are absorbed by the oligopeptide transporter (PepT1), fraction absorbed (F) of cephalosporin antibiotics was predicted from in vitro uptake into rat intestinal brush border membrane vesicles (BBMV). Using in vitro uptake data, F values of cephalosporins in humans were predicted using the equation derived from the complete radial mixing (CRM) model, which was proposed by Amidon et al. (Amidon et al., J. Pharm. Sci. 69 (1980) 1369). In the present study, uptake into BBMV was measured at 25 and 4 degrees C in the presence of an H+ -gradient, and the uptake clearance (CLuptake) was calculated. Clearance for the uptake mediated by PepT1 (DeltaCLuptake) was then calculated as CLuptake at 25 degrees C minus that at 4 degrees C. When DeltaCLuptake and F values were analyzed according to the present equation, fairly good correlation between DeltaCLuptake and F was observed. It was further demonstrated that the present method may be able to quantitatively predict F values of cephalosporins by using several cephalosporins as standards.
Kohda-Shimizu
R
R
School of Pharmaceutical Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, 108-8641, Tokyo, Japan.
Li
Y H
YH
Shitara
Y
Y
Ito
K
K
Tsuda
Y
Y
Yamada
H
H
Itoh
T
T
D000042:Absorption; D000818:Animals; D002352:Carrier Proteins / Q000493:pharmacokinetics*; D002511:Cephalosporins / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid; D006801:Humans; D008871:Microvilli / Q000378:metabolism*; D000074011:Peptide Transporter 1; D011237:Predictive Value of Tests; D051381:Rats; D027981:Symporters; D013696:Temperature
D002352:Carrier Proteins; D002511:Cephalosporins; D000074011:Peptide Transporter 1; C082186:SLC15A1 protein, human; C489940:Slc15a1 protein, rat; D027981:Symporters