Hepatic pharmacokinetics of propranolol in rats with adjuvant-induced systemic inflammation

Abstract

Systemic inflammation is known to affect drug disposition in the liver. This study sought to relate and quantitate changes in hepatic pharmacokinetics of propranolol with changes in hepatic architecture and physiology in adjuvant-treated rats. Transmission electron microscopy was used to assess morphological changes in mitochondria and lysosomes of adjuvant-treated rat livers. The disposition of propranolol was assessed in the perfused rat liver using the multiple indicator dilution technique. Hepatic extraction and mean transit time were determined from outflow-concentration profiles using a nonparametric method. Kinetic parameters were derived from a two-phase physiologically based organ pharmacokinetic model. Possible relationships were then explored between the changes in hepatic drug disposition and cytochrome P-450 activity and iron concentration. Adjuvant treatment induced the appearance of mitochondrial inclusions/tubularization and irregularly shaped lysosomes in rat livers. Livers from adjuvant-treated rats had (relative to normal) significantly higher alpha(1)-acid glycoprotein (orosomucoid) and iron tissue concentrations but lower cytochrome P-450 content. The hepatic extraction, metabolism, and ion trapping of propranolol were significantly impaired in adjuvant-treated rats and could be correlated with altered iron store and cytochrome P-450 activity. It is concluded that adjuvant-induced systemic inflammation alters hepatocellular morphology and biochemistry and consequently influences hepatic disposition of propranolol.

Hepatic Pharmacokinetics of Cationic Drugs in a High-Fat Emulsion-Induced Rat Model of Nonalcoholic Steatohepatitis

“…Hepatocyte permeability, intrinsic metabolic clearance, ion trapping, and microsomal binding were all changed in diseased livers (Siebert et al, 2004). An altered hepatic cytochrome P450 (P450) concentration was also seen in adjuvant-induced systemic inflammation (Hung et al, 2006).…”

Lactobacillus acidophilus Protected Organs in Experimental Arthritis by Regulating the Pro-inflammatory Cytokines

“…Their concentrations were increased in case of group II, III and VI animals (results have not shown here). Due to arthritis, walls of liver become leaky therefore enzyme concentration in arthritic condition increases [21,22]. Histopathological analysis of liver corroborated these findings.…”

“…Inflammation in an organ may affect the overall homeostasis of the body. Studies have suggested that during inflammatory diseases, serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) increases [21], [22]. These enzymes assays are good indices of liver damage.…”

Adjuvant arthritis 50 years on: the impact of the 1956 article by C. M. Pearson, ‘Development of arthritis, periarthritis and periostitis in rats given adjuvants’

“…NSAIDs.] At yet another level, adjuvant treatments can systemically alter membrane transport of a drug into hepatocytes [34].…”

“…Mycobacterial adjuvants also perturb iron distribution most notably in the liver [34]. An excess of ferritin accumulates, anaemia may ensue, and the production of some ironcontaining cytochromes is compromised.…”