Effects of perfusate flow rate on measured blood volume, disse space, intracellular water space, and drug extraction in the perfused rat liver preparation: characterization by the multiple indicator dilution technique.
The effect of hepatic blood flow on the elimination of several highly cleared substrates was studied in the once-through perfused rat liver preparation. A constant and low input concentration of ethanol (2.0 mM), [14C]-phenacetin and [3H]-acetaminophen (0.36 and 0.14 microM, respectively), or meperidine (8.1 microM) was delivered once-through the rat liver preparation in five flow periods (greater than 35 min each); control flow periods at 12 ml/min were interrupted by flow changes to 8 or 16 ml/min. The steady-state hepatic availabilities (F or outflow survivals) at 12 ml/min were ethanol, 0.075 +/- 0.038; [14C]-phenacetin, 0.15 +/- 0.059; [3H]-acetaminophen, 0.34 +/- 0.051; meperidine, 0.047 +/- 0.017. Flow-induced changes were different among the compounds: with reduced flow (8 ml/min), F was decreased for ethanol (0.061 +/- 0.032) and [3H]-acetaminophen (0.28 +/- 0.051), as expected, but was increased for [14C]-phenacetin (0.20 +/- 0.068) and meperidine (0.05 +/- 0.03); with an elevation of flow (to 16 ml/min), F was increased for all compounds, as expected of shorter sojourn times: ethanol, 0.13 +/- 0.065; [14C]-phenacetin, 0.22 +/- 0.062; [3H]-acetaminophen, 0.43 +/- 0.063; meperidine, 0.055 +/- 0.022. A marked increase in F for ethanol had occurred when flow changed from 12 to 16 ml/min due to nonlinear metabolism; the latter was confirmed by a reduction in the extraction ratios at increasing concentrations (1.8 to 11.4 mM); this condition was not present for the other compounds. In order to explain the observations, we used the multiple indicator dilution technique to investigate the flow-induced behaviors of tissue distribution spaces of vascular and intracellular references in the perfused rat liver preparation.
Pang
K S
KS
Faculty of Pharmacy, University of Toronto, Ontario, Canada.
Lee
W F
WF
Cherry
W F
WF
Yuen
V
V
Accaputo
J
J
Fayz
S
S
Schwab
A J
AJ
Goresky
C A
CA
D000082:Acetaminophen / Q000493:pharmacokinetics; D000818:Animals; D001826:Body Fluids / Q000378:metabolism*; D000431:Ethanol / Q000493:pharmacokinetics; D066298:In Vitro Techniques; D007201:Indicator Dilution Techniques; D007424:Intracellular Fluid / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008102:Liver Circulation; D008297:Male; D008614:Meperidine / Q000493:pharmacokinetics; D008657:Metabolic Clearance Rate; D010477:Perfusion; D010599:Pharmacokinetics; D010615:Phenacetin / Q000493:pharmacokinetics; D051381:Rats; D011919:Rats, Inbred Strains
D000082:Acetaminophen; D000431:Ethanol; D008614:Meperidine; D010615:Phenacetin