Abstract
Enterohepatic Circulation (EHC) is the process by which bile acid are secreted from the liver into the bile, excreted into the small intestine and then reabsorbed back into the liver. This efflux process is spurred by drug saturation, which is a condition in which the rate of absorption of the drug is limited by the rate of transport to the liver or the rate of secretion into the bile. EHC plays a crucial role for several liver and gastrointestinal functions such as bile flow, solubilization and excretion of cholesterol, clearance of toxic molecules, intestinal absorption of lipophilic nutrients, as well as metabolic and antimicrobial effects. Despite its positive impact in human homeostasis,it is known that EHC can increase toxicity of drugs(due to incomplete elimination during recycling), increased risk of gallstones which result to systemic diseases such as cholelithiasis, bile duct cancer, pancreatic cancer and hepatotoxicity(drug liver injury). In the formulation of a Physiologically Based Pharmacokinetic Model of EHC Drugs with Saturation Kinetics is formulated. The model is affected by secreted drug in the hepatocyte and gastrointestinal compartment with delay effect on metabolites. The drug toxicity threshold parameter and delay effect accounting for gallbladder and intestine disorder(alter the rate of bile circulation) will be discussed. The model is rigorously analyzed on Drug Free Equilibria, Drug Saturation Equilibria, Toxicity Equilibria and Drug Reabsorption Equilibria. Threshold value for Pathological parameter for which there exist a trans from Hoph bifurcation to periodic system was established.
The direction of Stability (super critical and subcritical) was also established. Global and Local stabilities were also investigated. The results from the analysis showed that drug saturation induces toxicity in the
absence of pathological defect parameters when Drug Toxicity Number (DTN) is xi greater than one .Whereas in the presence of pathological parameters (Mild Case), Drug Toxicity does not annul the physiological state of the compartments hence cannot effect drug reabsorption. There exist a threshold for pathological parameters for which drug reabsorption occurs, and defect in physiological compartment progresses from mild to acute case when pathological parameters exceed this threshold i.e τ1 + τ2 > v2+2m2 η2 Hoph bifurcation analysis on the Drug Free and Drug Saturation Equilibria showed that there exist an upper bound for which the system remains asymptotically stable. Numerical results obtained from this work will provide a framework for Pharmaceutical Policies and decisions on EHC.Enterohepatic Circulation (EHC) is the process by which bile acid are secreted from the liver into the bile, excreted into the small intestine and then reabsorbed back into the liver. This efflux process is spurred by drug saturation, which is a condition in
which the rate of absorption of the drug is limited by the rate of transport to the liver or the rate of secretion into the bile. EHC plays a crucial role for several liver and gastrointestinal functions such as bile flow, solubilization and excretion of cholesterol, clearance of toxic molecules, intestinal absorption of lipophilic nutrients, as well as metabolic and antimicrobial effects. Despite its positive impact in human homeostasis,
it is known that EHC can increase toxicity of drugs(due to incomplete elimination during recycling), increased risk of gallstones which result to systemic diseases such as cholelithiasis, bile duct cancer, pancreatic cancer and hepatotoxicity(drug liver injury). In the formulation of a Physiologically Based Pharmacokinetic Model of EHC Drugs with Saturation Kinetics is formulated. The model is affected by secreted drug in the hepatocyte and gastrointestinal compartment with delay effect on metabolites. The drug toxicity threshold parameter and delay effect accounting for gallbladder and intestine disorder(alter the rate of bile circulation) will be discussed. The model is rigorously analyzed on Drug Free Equilibria, Drug Saturation Equilibria, Toxicity Equilibria and Drug Reabsorption Equilibria. Threshold value for Pathological parameter for which there exist a trans from Hoph bifurcation to periodic system was established. The direction of Stability (super critical and subcritical) was also established. Global and Local stabilities were also investigated.
The results from the analysis showed that drug saturation induces toxicity in the absence of pathological defect parameters when Drug Toxicity Number (DTN) is xi greater than one .Whereas in the presence of pathological parameters (Mild Case), Drug Toxicity does not annul the physiological state of the compartments hence cannot effect drug reabsorption. There exist a threshold for pathological parameters
for which drug reabsorption occurs, and defect in physiological compartment progresses from mild to acute case when pathological parameters exceed this threshold i.e τ1 + τ2 > v2+2m2 η2. Hoph bifurcation analysis on the Drug Free and Drug Saturation Equilibria showed that there exist an upper bound for which the system remains asymptotically stable. Numerical results obtained from this work will provide a framework for Pharmaceutical Policies and decisions on EHC.