Effect of erythrocyte binding on elimination of harmol by the isolated perfused rat liver

J Pharm Sci. 1996 Jan;85(1):40-4. doi: 10.1021/js950282e.


The effect on the hepatic elimination rate of drug bound to erythrocytes and to albumin was compared with harmol, a relatively hydrophilic drug of high hepatic intrinsic clearance, in the single-pass isolated perfused rat liver preparation (n = 12). The steady-state hepatic extraction ratio (E) of harmol (50 microM) was measured during three consecutive 35-min periods with three different perfusates: Krebs-Henseleit buffer, buffer containing bovine serum albumin (2%), and buffer containing washed human erythrocytes (10%) perfused at 5 mL/min/g liver in randomized order. The mean unbound fraction (fu) of harmol in the latter two perfusates was 0.55 +/- 0.07 and 0.62 +/- 0.08, respectively, and the mean E for the three perfusates were 0.85 +/- 0.06, 0.62 +/- 0.07, and 0.71 +/- 0.08, respectively. The sinusoidal model fitted the relationship between E and fu better than the venous equilibrium model. Four further experiments, with perfusates of buffer, buffer + 2% albumin, and buffer + 4% albumin, confirmed that harmol elimination conformed to the sinusoidal model. For each of the 12 experiments that used erythrocyte perfusate, E and fu data from each of the two non-erythrocyte perfusates were used to predict E for the erythrocyte perfusate at the observed fu of 0.62, with the sinusoidal model. There was no significant difference between the observed (0.71 +/- 0.08) and predicted (0.68 +/- 0.10) E values (p > 0.05). This result suggests that release of harmol from erythrocytes is not a rate-limiting factor in the hepatic elimination of harmol, and that plasma membrane permeability does not contribute readily to a red cell carriage effect, at least with moderately polar and small molecules.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Erythrocytes / metabolism*
  • Harmine / analogs & derivatives*
  • Harmine / blood
  • Harmine / pharmacokinetics
  • Liver / metabolism*
  • Male
  • Oxygen / administration & dosage
  • Oxygen / metabolism
  • Perfusion
  • Rats
  • Rats, Sprague-Dawley
  • Serum Albumin, Bovine / metabolism


  • Serum Albumin, Bovine
  • harmol
  • Harmine
  • Oxygen