Effect of Erythrocyte Binding on Elimination of Harmol by the Isolated Perfused Rat Liver

Abstract

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.

In Vitro and in Vivo Studies on Plasma-to-Blood Ratio of Paclitaxel in Human, Rabbit and Rat Blood Fractions

“…The carriage effect of red cell would play an important role of potential barrier, which acts as a shield against drug release and elimination. 17,18) The bound, partitioned and unbound drug fractions in blood coexist and equilibria are maintained between the unbound and bound species. In contrast to the unbound drug molecules, the bound or partitioned molecules are not immediately available for elimination.…”

Effect of erythrocytes on the hepatic distribution kinetics of antipyrine

“…Although this was the case for urea [2], monohydric alcohols [3], xenon [4], salicylamide [5] and harmol [6], altered hepatic disposition has been observed for a number compounds including doxorubicin [7], propranolol [8], tacrolimus [9], acetaminophen [10], and 4-methylumbelliferyl sulfate [11]. More recently, Goresky et al [12] reported that lactate within red blood cells does not change with plasma fast enough to be available for material hepatocellular uptake during single pass through this organ.…”