Prediction of in vivo tissue distribution from in vitro data. 3. Correlation between in vitro and in vivo tissue distribution of a homologous series of nine 5-n-alkyl-5-ethyl barbituric acids.
OBJECTIVE
To evaluate the ability to determine accurate in vivo tissue-to-unbound plasma distribution coefficients (Kpue) from in vitro data.


METHODS
Fresh pieces of fifteen rat tissues/organs were incubated at 37 degrees C with a homologous series of nine barbiturates covering a wide range of lipophilicity (Log P 0.02 to 4.13). Steady-state in vivo Kpue values were estimated from the tissue and plasma concentrations following simultaneous dosing by constant rate i.v. infusion of all nine barbiturates. Drug concentrations in the tissues and media were determined by HPLC with UV or mass spectrometric detection.


RESULTS
The pharmacokinetics of the barbiturate series following constant rate i.v. infusion indicated a range of clearance (0.49 to 30 ml x min(-1) x kg(-1)) and volume of distribution at steady state (0.51 to 1.9 l x kg(-1)) values. Good agreement was observed between the in vitro and in vivo Kpu values, although for the most lipophilic barbiturates the in vitro data underpredicted the in vivo tissue distribution for all tissues.


CONCLUSIONS
The in vitro system for predicting the extent of in vivo tissue distribution works well for compounds of widely differing lipophilicity, although for the most lipophilic drugs it may result in an underprediction of in vivo values.
Ballard
Peter
P
Discovery-DMPK, Mereside, AstraZeneca, Alderley Park, Cheshire, SK10 4TG, United Kingdom. peter.ballard@astrazeneca.com
Leahy
David E
DE
Rowland
Malcolm
M
D000818:Animals; D001463:Barbiturates / Q000493:pharmacokinetics*; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D002851:Chromatography, High Pressure Liquid; D006207:Half-Life; D006863:Hydrogen-Ion Concentration; D007202:Indicators and Reagents; D007262:Infusions, Intravenous; D008297:Male; D013058:Mass Spectrometry; D008970:Molecular Weight; D051381:Rats; D017208:Rats, Wistar; D013056:Spectrophotometry, Ultraviolet; D013329:Structure-Activity Relationship; D014018:Tissue Distribution
D001463:Barbiturates; D007202:Indicators and Reagents