Prediction of in vivo tissue distribution from in vitro data 1. Experiments with markers of aqueous spaces.
OBJECTIVE
The aim of this study was to evaluate the ability of an in vitro method of tissue distribution to accurately predict total water and extracellular aqueous spaces using marker compounds urea and inulin.


METHODS
Slices (50-200 mg) of all the major tissues in the rat were incubated with Hanks/HEPES pH7.4 buffer containing 14C-urea and 3H-inulin for 2 h at 37 degrees C. Tissue weight was noted before and after incubation and the tissue-to-buffer ratios determined.


RESULTS
14C-Urea Kp estimates were generally greater than total tissue water due to tissue swelling, which varied widely among the tissues, up to 41% in muscle. In most cases, Kp values were much closer to in vivo values after correcting for the 14C-urea in the imbibed media (Kpcorr). The method was able to distinguish between 14C-urea and 3H-inulin Kp values and indicated that inulin occupied a smaller space than urea, which for the majority of tissues corresponded to the extracellular space.


CONCLUSIONS
The Kp(corr) values for 14C-urea and Kp for 3H-inulin were consistent with total tissue water and extracellular space for the majority of tissues studied, indicating their suitability as marker compounds for checking the viability of this in vitro method for estimating tissue distribution.
Ballard
P
P
Discovery-DMPK, AstraZeneca, Alderley Park, Cheshire, United Kingdom. peter.ballard@astrazeneca.com
Leahy
D E
DE
Rowland
M
M
D000818:Animals; D066298:In Vitro Techniques; D007444:Inulin / Q000493:pharmacokinetics*; D051381:Rats; D014018:Tissue Distribution; D014508:Urea / Q000493:pharmacokinetics*
D014508:Urea; D007444:Inulin