EFFECT OF ERYTHROCYTE BINDING ON ELIMINATION OF HARMOL BY THE ISOLATED-PERFUSED RAT-LIVER

The effect on the hepatic elimination rate of drug bound to erythrocyt es and to albumin was compared with harmol, a relatively hydrophilic d rug of high hepatic intrinsic clearance, in the single-pass isolated p erfused rat liver preparation (n 12). The steady-state hepatic extract ion ratio (E) of harmol (50 mu M) was measured during three consecutiv e 35-min periods with three different perfusates: Krebs-Henseleit buff er, buffer containing bovine serum albumin (2%), and buffer containing washed human erythrocytes (10%) perfused at 5 mL/min/g liver in rando mized order. The mean unbound fraction (fu) of harmol in the latter tw o perfusates was 0.55 +/- 0.07 and 0.62 +/- 0.08, respectively, and th e mean E for the three perfusates were 0.85 +/- 0.06, 0.62 +/- 0.07, a nd 0.71 +/- 0.08, respectively. The sinusoidal model fitted the relati onship between E and f(u) better than the venous equilibrium model. Fo ur 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 ery throcyte perfusate, E and f(u) data from each of the two non-erythrocy te perfusates were used to predict E for the erythrocyte perfusate at the observed f(u) of 0.62, with the sinusoidal model. There was no sig nificant 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 hepat ic elimination of harmol, and that plasma membrane permeability does n ot contribute readily to a red cell carriage effect, at least with mod erately polar and small molecules.