Relationship between lipophilicity and hepatic dispersion and distribution for a homologous series of barbiturates in the isolated perfused in situ rat liver.
The hepatic disposition kinetics of a homologous series of 5-n-alkyl-5-ethyl barbituric acids (methyl, ethyl, propyl, butyl, and pentyl) were determined using a single-pass perfused in situ rat liver preparation. The perfusion experiments were conducted using protein-free Krebs bicarbonate medium, delivered at a constant flow of 15 ml/min. Each barbiturate was injected separately into the portal vein as a rapid bolus (25 micrograms/50 microliters) at appropriate intervals in a random order. The venous outflow concentrations of the barbiturates were determined by HPLC. A nonlinear least squares program was used to fit the axial dispersion model of hepatic elimination to the outflow profiles. With increasing length of the alkyl chain, there was a significant increase in the volume of distribution in the liver (0.85 +/- 0.12 ml/g for methyl and 4.87 +/- 1.27 ml/g for pentyl), which led to an increased organ mean transit time (35 +/- 2.4 sec for methyl and 223 +/- 32.8 sec for pentyl). The increased volume of distribution may have arisen from greater binding to intracellular proteins and/or greater partitioning into lipophilic components of hepatic tissue. The dispersion numbers of this homologous series, a measurement of relative axial spreading, were similar (0.28-0.39), despite the wide range of log P values (0.02-2.23) among them. The similarity between the dispersion number for each barbiturate and that for reference markers (erythrocytes, albumin, and water) suggests that the relative axial spreading of these barbiturates is determined primarily by the heterogeneity of the hepatic vasculatory system.
Chou
C H
CH
Department of Pharmacy, University of Manchester, U.K.
Evans
A M
AM
Fornasini
G
G
Rowland
M
M
D000818:Animals; D001463:Barbiturates / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics*; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism*; D008297:Male; D008432:Mathematical Computing; D010477:Perfusion; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D014018:Tissue Distribution
D001463:Barbiturates