Prediction of whole-body metabolic clearance of drugs through the combined use of slices from rat liver, lung, kidney, small intestine and colon.
1: The aim was to investigate whether precision-cut rat tissue slices could be used to predict metabolic drug clearance in vivo. To obtain a complete picture, slices not only from liver, but also from lung, kidney, small intestine and colon were included. 2: The metabolic clearances of 7-ethoxycoumarin, 7-hydroxycoumarin, testosterone, methyltestosterone and warfarin were determined by measuring the disappearance of these compounds during incubation with slices prepared from liver, lung, kidney, small intestine and colon. 3: The total in vitro metabolic clearance was determined by adding the individual in vitro organ clearances from the slices. Prediction based on the in vitro clearance was within an order of magnitude to the corresponding in vivo values. Interestingly, the relative contribution of extrahepatic metabolic clearance of the studied compounds to total clearance was remarkably high, ranging from 35 to 72% of the total metabolic clearance. 4: It is concluded that the model of multi-organ precision-cut slices is a useful in vitro tool for prediction of in vivo metabolic clearance. In addition, it provides information about the relative contribution of the liver, lung, kidney, small intestine and colon to the total metabolic clearance.
De Kanter
R
R
Pharmacia Italia SpA, gruppo Pfizer, Inc., Department of Pharmacokinetics, Dynamics and Metabolism, Viale Pasteur 10, I-20014 Nerviano (MI), Italy. ruben.dekanter@pharmacia.com
Monshouwer
M
M
Draaisma
A L
AL
De Jager
M H
MH
de Graaf
I A M
IA
Proost
J H
JH
Meijer
D K F
DK
Groothuis
G M M
GM
D000818:Animals; D001711:Biotransformation; D003106:Colon / Q000378:metabolism; D003374:Coumarins / Q000378:metabolism* / Q000493:pharmacokinetics*; D066298:In Vitro Techniques; D007421:Intestine, Small / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D008297:Male; D008867:Microtomy; D009928:Organ Specificity; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D011237:Predictive Value of Tests; D051381:Rats; D017208:Rats, Wistar; D014468:Umbelliferones / Q000378:metabolism* / Q000493:pharmacokinetics*
D003374:Coumarins; D004364:Pharmaceutical Preparations; D014468:Umbelliferones; C017299:7-ethoxycoumarin; C031477:7-hydroxycoumarin