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

• Published in: Journal of pharmaceutical sciences Vol. 85; no. 1; pp. 40 - 44
• Main Authors: Morgan, Denis J., Guttmann, Aaron, Peter Watson, R.G., Ghabrial, Hany, Elliott, Susan L., Smallwood, Richard A.
• Format: Journal Article
• Language: English
• Published: New York Elsevier Inc 01.01.1996; John Wiley & Sons, Inc; Wiley; American Pharmaceutical Association
• Subjects: Animals; Biological and medical sciences; Cells, Cultured; Erythrocytes - metabolism; General pharmacology; Harmine - analogs & derivatives; Harmine - blood; Harmine - pharmacokinetics; Liver - metabolism; Male; Medical sciences; Oxygen - administration & dosage; Oxygen - metabolism; Perfusion; Pharmacokinetics. Pharmacogenetics. Drug-receptor interactions; Pharmacology. Drug treatments; Rats; Rats, Sprague-Dawley; Serum Albumin, Bovine - metabolism; Drug; Vertebrata; Mammalia; Rat; Animal; Liver; Rodentia; Elimination; Albumin; Red blood cell; In vitro; Bound form
• ISSN: 0022-3549; 1520-6017
• 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 μM) 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.