Telmisartan Self-Nanoemulsifying Drug Delivery System, Compared With Standard Telmisartan, More Effectively Improves Hepatic Fibrosis in Rats

Abstract

Background: This study was designed to examine effects of telmisartan; an angiotensin receptor blocker; self-nanoemulsifying drug delivery system (SNEDDS) in reversing already-established hepatic fibrosis.

Method: Forty rats were given thioacetamide (200 mg/kg, intraperitoneally) twice/week for 8 weeks then divided into 5 groups (n = 8), PC and 4 treated groups. Treatments were given orally for another 2 months as follows: telmisartan low and high doses (TL and TH: 1.8 and 3.6 mg/kg/day) and telmisartan SNEDDS at the same doses (TLS and THS). At end of treatment, blood was obtained and liver was isolated.

Results: Rats showed significant elevations of plasma ALT and AST and hepatic IL-6, TNF-α, and MDA, significant reductions of plasma albumin, hepatic GSH, and body weight, and hepatic histopathological damage. All treatments except for TL significantly reversed these thioacetamide-induced changes. THS group showed significant differences from all groups. Regarding ratio of free telmisartan concentration in hepatic homogenate to that of plasma, TH and TLS groups showed non-significant variation between each other while THS group showed significant differences from them. No significant changes were detected in blood pressure, hemoglobin, white blood cells, and platelets.

Conclusion: Telmisartan SNEDDS, compared with telmisartan, more effectively reversed chronic hepatic fibrosis with good safety profile.

Keywords: liver fibrosis; telmisartan; thioacetamide.

Figure 1.

Transmission electron microscope (TEM) of Telmisartan SNEDDS formula (X 30,000 magnification).

Figure 2.

Effects of telmisartan low and high doses as standard drug (TL, TH) and as SNEDDS formula (TLS, THS) on plasma levels of ALT and AST in TAA-induced hepatic fibrosis rats (n = 8). Data are expressed as mean ± SEM. *: P < 0.05 vs. Normal control (NC), ^#: P < 0.05 vs. Positive control (PC) and TL, ^{^}: P < 0.05 vs. TH & TLS.

Figure 3.

Microphotographs of liver sections of rats of: (NC) normal control group showing normal hepatic structure and hepatocytes around the central vein (CV). (PC) thioacetamide group showing definitive hepatic lobulation (arrows), marked inflammatory infiltration (stars), and degenerative hepatocytes. (TL) telmisartan low dose group showing no improvement. (TH) telmisartan high dose group and (TLS) telmisartan low dose-SNEDDS showing mild improvement with moderate hepatic lobulation (arrows), inflammatory infiltrates (stars), and hepatocyte degeneration. (THS) telmisartan high-SNEDDS group showing moderate protection with mild inflammatory infiltrate (stars) and degenerative appearance of the hepatocytes (H&E, High power (X20)).

Figure 4.

Representative MRM transition chromatograms of telmisartan in: A. Plasma and B. Liver homogenate.

Figure 5.

The ratio of the free telmisartan concentration in hepatic homogenate to that of plasma (H/P ratio) with telmisartan low and high doses as raw drug (TL, TH) and as SNEDDS formula (TLS, THS) in TAA-induced hepatic fibrosis rats (n = 8). Data are expressed as mean ± SEM. *: P < 0.05 vs. TL, ^#: P < 0.05 vs. TH, TLS.