Intestinal absorption and hepatic elimination of drugs in high‐fat high‐cholesterol diet‐induced non‐alcoholic steatohepatitis rats: exemplified by simvastatin

Abstract

Background and Purpose: Altered drug pharmacokinetics is a significant concern in non-alcoholic steatohepatitis (NASH) patients. Although high-fat high-cholesterol (HFHC) diet-induced NASH (HFHC-NASH) rats could simulate the typical dysregulation of cholesterol in NASH patients, experimental investigation on the altered drug pharmacokinetics in this model are limited. Thus, the present study comprehensive investigates the nature of such altered pharmacokinetics using simvastatin as the model drug.Experimental Approach: Pharmacokinetic profiles of simvastatin and its active metabolite simvastatin acid together with compartmental pharmacokinetic modelling were used to identify the key factors involved in the altered pharmacokinetics of simvastatin in HFHC-NASH rats. Experimental investigations via in situ single-pass intestinal perfusion and intrahepatic injection of simvastatin were carried out. Histology, Ces1 activities and mRNA/protein levels of Oatp1b2/CYP2c11/P-gp in the small intestine/liver of healthy and HFHC-NASH rats were compared. Key Results: Reduced intestinal absorption and more extensive hepatic elimination in HFHC-NASH rats resulted in less systemic exposures of simvastatin/simvastatin acid.In the small intestine of HFHC-NASH rats, thicker intestinal wall with more collagen fibres, increased Ces1 activity and up-regulated P-gp protein decreased the permeability of simvastatin, accelerated the hydrolysis of simvastatin and promoted the efflux of simvastatin acid respectively. In the liver of HFHC-NASH rats, higher hepatic P-gp expression accelerated the hepatic elimination of simvastatin. Conclusion and Implications:Altered histology, Ces1 activity and P-gp expression in the small intestine/liver were identified to be the major contributing factors leading to less systemic exposure of drugs in HFHC-NASH rats, which may be applicable to NASH patients.

Erythropoietin hyporesponsiveness in non‐alcoholic fatty liver disease

“…During the 12‐week feeding, body weight gains of rats that fed with the HFHC diet (n = 6) were 496.3 ± 5.27 g and showed no significant difference with 501.3 ± 17.7 g of the rats fed the normal chow (n = 6) (Figure 1B). Meanwhile, significantly higher ALT, AST, LDL and total cholesterol levels, and lower HDL levels were observed in the rats that fed with the HFHC diet (Figure 1C), indicating the occurrence of liver injury and hyperlipidemia as described before 36,37 . H&E staining results in Figure 1D demonstrate severe hepatic steatosis, moderate inflammation in the hepatic lobule and a few ballooning degradations of hepatocytes in the HFHC‐NAFLD rats.…”

“…Meanwhile, significantly higher ALT, AST, LDL and total cholesterol levels, and lower HDL levels were observed in the rats that fed with the HFHC diet (Figure 1C), indicating the occurrence of liver injury and hyperlipidemia as described before. 36,37 H&E staining results in Figure 1D demonstrate severe hepatic steatosis, moderate inflammation in the hepatic lobule and a few ballooning degradations of hepatocytes in the HFHC-NAFLD rats. Those symptoms in rats could be identified as NAFLD.…”

“…One group of rats was fed with an HFHC diet consisting of 80.5% normal chow, 2% cholesterol, 7% lard, 10% yolk powder and 0.5% sodium cholate for 12 weeks as previously described. 36,37 The other group of rats was fed with normal chow for 12 weeks. During the 12-week feeding, body weight and haematological response were assessed weekly.…”

“…A total of 24 SD rats were randomly divided into two groups with 12 rats in each. One group of rats was fed with an HFHC diet consisting of 80.5% normal chow, 2% cholesterol, 7% lard, 10% yolk powder and 0.5% sodium cholate for 12 weeks as previously described 36,37 . The other group of rats was fed with normal chow for 12 weeks.…”

Digoxin Pharmacokinetics in Patients with Obesity Before and After a Gastric Bypass or a Strict Diet Compared with Normal Weight Individuals

“…In line with this finding, Hardwick et al found an increased expression of P-gp in human liver samples with the progression of NAFLD [ 28 ]. Other studies have also demonstrated a higher hepatic P-gp expression, as well as lower AUC following intravenous and oral dosing of digoxin in rats with NAFLD [ 29 , 30 ]. Nevertheless, in the study by Abernethy et al, there was no difference in the clearance of digoxin between patients with obesity and normal weight controls following intravenous administration [ 31 ].…”