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

Abstract

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.

Interplay of Phase II Enzymes and Transporters in Futile Cycling: Influence of Multidrug Resistance-Associated Protein 2-Mediated Excretion of Estradiol 17β-d-Glucuronide and Its 3-Sulfate Metabolite on Net Sulfation in Perfused TR−and Wistar Rat Liver Preparations

“…2), the published value of CL in for E 2 17G (546 ml/min) of Sun et al (2006) was assumed to hold here for both the Wistar and TR Ϫ livers. When influx is fast in relation to the flow rate, a Averaged value from t ϭ 0 (200 ml) to time ϭ 2 h. b From multiple indicator dilution studies (Pang et al, 1988). c Sum of bile volume of canaliculi (0.004 ml/g liver) and bile cannula volume (20 cm of polypropylene tubing with i.d.…”

Vascular Binding, Blood Flow, Transporter, and Enzyme Interactions on the Processing of Digoxin in Rat Liver

“…B, on and off binding constants for digoxin with red cell were set as zero (kЈ rp ϭ k pr ϭ 0) (OO •• OO), and binding to BSA was absent (f p ϭ 1) (-----). Pang et al (1988). c Cellular water space of liver, taken from Pang et al (1988).…”

“…where ␥ is the ratio of the interstitial or Disse space to the sinusoidal plasma space (Pang et al, 1988). Rat Liver Perfusion Studies.…”

Physiologically Based Synthetic Models of Hepatic Disposition

“…In the in silico experiments that follow, SUCROSE and ANTIPYRINE were both co-administered and administered separately. Because ANTIPYRINE crosses into CELLS, whereas SUCROSE cannot, the outflow profile for SUCROSE is much more sensitive to SS geometry than is the profile for ANTIPYRINE, and that is a reason that it has been traditionally used as an extravascular marker (29,30). Consequently, parameterizations were done as follows.…”