Age-related pseudocapillarization of the liver sinusoidal endothelium impairs the hepatic clearance of acetaminophen in rats

Abstract

We investigated the effect of age-related pseudocapillarization of the liver sinusoidal endothelium on the hepatic disposition of acetaminophen. The multiple indicator dilution technique assessed the hepatic disposition of tracer (14)C-acetaminophen and reference markers in isolated perfused livers of young (n = 11) and old (n = 12) rats. Electron microscopy confirmed defenestration of the sinusoidal endothelium in old rats compared with young rats. Acetaminophen recovery following a single pass through the liver was significantly increased in old rats (0.64 ± 0.04, old; 0.59 ± 0.05, young; p < .05). In old age, there was significant reduction of the intercompartmental rate constant k(1) (0.34 ± 0.10 s(-1), old; 0.61 ± 0.38 s(-1), young; p < .05) and the permeability-surface area product for the transfer of acetaminophen across the sinusoidal endothelium (0.034 ± 0.006 mL/s/g, old; 0.048 ± 0.014 mL/s/g, young; p < .005). There was no difference in k(3), the measure of sequestration of acetaminophen that reflects enzyme activity. Age-related pseudocapillarization of the liver sinusoid resulted in increased acetaminophen recovery and decreased transfer of acetaminophen into the liver.

Figure 1.

Representative dose-normalized outflow curves for acetaminophen, sucrose, and Evans Blue from multiple indicator dilution experiments in isolated perfused rat livers from a young (A) and old (B) rat livers perfused with 2% bovine serum albumin.

Figure 2.

Representative curve demonstrating the relationship between time and the early extraction of acetaminophen for a young and an old rat. The reference marker is Evans Blue.

Figure 3.

Representative scanning electron micrographs of hepatic sinusoids. The sinusoidal endothelium of the young animal (A) is perforated with fenestrations in clusters (“sieve plates”). The sinusoidal endothelium of the old animal (B) has a reduced number of fenestrations.