Pharmacokinetics of diaspirin cross-linked haemoglobin in a rat model of hepatic cirrhosis.
The aim of the study was to evaluate the effect of cirrhosis on the disposition of the haemoglobin-based oxygen carrier, diaspirin cross-linked haemoglobin (DCLHb). Cirrhosis was induced in male Sprague-Dawley rats (200-250 g) by inhalational exposure to carbon tetrachloride (CCl4), over a period of 6 weeks. Pharmacokinetic evaluation was performed after a single intravenous bolus administration of DCLHb (400 mg kg(-1)). Serum biochemistry, including aspartate transaminase, alkaline phosphatase, bile acids, serum albumin, and serum creatinine, were measured in CCl4-treated (n = 6) and age-matched control (n = 6) rats. After 6 weeks, the jugular vein and carotid artery were cannulated for bolus DCLHb administration (400 mg kg(-1)) and blood sampling, respectively, in both groups of rats. Cirrhosis produced significant (P < 0.05) elevations in alkaline phosphatase (497.4 +/- 84.8 U L(-1) vs 241.2 +/- 5.1 U L(-1)), aspartate transaminase (920.5 +/- 190.9 U L(-1) vs 238.2 +/- 118.1 U L(-1)) and bile acids (333.8 +/- 77.3 mg dL(-1) vs 43.8 +/- 4.2 mg dL(-1)) compared with the control group. No significant renal dysfunction was observed as a result of CCl4 exposure. Plasma DCLHb concentrations declined approximately log-linearly. Systemic clearance of DCLHb was estimated to be 2.2 +/- 0.7 mL h(-1) in the treatment group and was slightly, but not significantly, less in the control group (3.6 +/- 1.7 mL h(-1)). There was also a trend toward a longer elimination half-life in the treatment group (4.7 +/- 2.2 h) compared with the control group (3.8 +/- 0.8 h), although this difference was not statistically significant. Cirrhosis does not significantly alter the disposition of DCLHb perhaps due to increased extra-hepatic metabolism by the reticulo-endothelial system.
Department of Pharmaceutics and Pharmacodynamics, The University of Illinois at Chicago, 60612, USA.
R
R
Palaparthy
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H
Kastrissios
A
A
Gulati
D000818:Animals; D019540:Area Under Curve; D001241:Aspirin / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics*; D015415:Biomarkers; D001702:Biopharmaceutics; D001802:Blood Substitutes / Q000493:pharmacokinetics*; D002252:Carbon Tetrachloride Poisoning / Q000378:metabolism; D006207:Half-Life; D006454:Hemoglobins / Q000493:pharmacokinetics*; D008106:Liver Cirrhosis, Experimental / Q000378:metabolism*; D008111:Liver Function Tests; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley
D015415:Biomarkers; D001802:Blood Substitutes; D006454:Hemoglobins; C083478:diaspirin-cross-linked hemoglobin; D001241:Aspirin