Hepatic and Intestinal Changes in Rats Treated With T-0126, a Microsomal Triglyceride Transfer Protein (Mtp) Inhibitor

Abstract

In the present study, we investigated the potential toxic effects of 2-week oral treatment with T-0126, a novel microsomal triglyceride transfer protein (MTP) inhibitor, on the liver and intestine in male and female rats. Administration of T-0126 decreased serum lipids and resulted in fat accumulation in the liver and the small intestine. In addition, slight changes in the liver, including an increase in serum aminotransferase (AST and ALT) activity, presence of focal inflammatory lesions, and prolongation of PT and APTT were observed after treatment with T-0126. These changes may be related to a mechanism based on malabsorption of fat, fat-soluble antioxidants, and vitamin K, although we cannot exclude other potential mechanisms such as direct cytotoxicity of T-0126.

A Small-Molecule Inhibitor of Enterocytic Microsomal Triglyceride Transfer Protein, SLx-4090: Biochemical, Pharmacodynamic, Pharmacokinetic, and Safety Profile

“…In contrast, the systemic MTP inhibitor implitapide significantly elevated liver transaminases in these mice (P. Sweetnam, unpublished data). Unlike other MTP inhibitors (Chandler et al, 2003;Ueshima et al, 2005;Miyazaki et al, 2007), SLx-4090 also significantly increased HDL-C.…”

“…Unfortunately, MTP is also found in a number of additional organs with notably jpet.aspetjournals.org high levels in the liver, retina, and heart (Borén et al, 1998;Li et al, 2005). Inhibition of hepatic MTP decreases the ability of the liver to rid itself of fat, and chronic treatment with first-generation MTP inhibitors resulted in unacceptable rises in liver transaminases and hepatic steatosis in rodent models and humans Lilly and Rader, 2007;Miyazaki et al, 2007;Wren et al, 2007). Inhibition of MTP in the heart and the retina may also elicit adverse effects (Borén et al, 1998;Li et al, 2005).…”

“…To further demonstrate the enterocytic specificity of SLx- (Chandler et al, 2003;Aggarwal et al, 2005;Lilly and Rader, 2007;Miyazaki et al, 2007), HFD ApoE(Ϫ/Ϫ) mice (Ueshima et al, 2005), and mice with intestinal-specific MTP deletion (Xie et al, 2006). ApoE(Ϫ/Ϫ) mice maintained on a HFD and SLx-4090 for 10 weeks had improved lipid profiles (lower baseline TG and total cholesterol and LDL-C and higher HDL-C levels) compared with vehicle-treated animals.…”

“…The major impediment to the development of clinically useful MTP inhibitors has been the rapid development of liver toxicities Lilly and Rader, 2007;Miyazaki et al, 2007). In contrast, SLx-4090 demonstrated no indication of hepatic damage from either a histological or a clinical chemistry perspective in toxicological studies as long as 90 days with doses as high as 1000 mg/kg (rat) or 100 mg/kg (dog) (P. Sweetnam, unpublished data).…”

“…These efforts led to the discovery of molecules that were potent inhibitors of hepatic MTP and proved very effective in reducing the ability of the liver to export VLDL-C (Wetterau et al, 1998;Roevens et al, 1999;Gruetzmann et al, 2000;Chandler et al, 2003;Aggarwal et al, 2005;Li et al, 2007). Unfortunately, blockade of hepatic MTP was quickly associated with a significant decrease in the ability of the liver to rid itself of fat, and administration of MTP inhibitors in clinical trials universally resulted in unacceptable rises in liver transaminases and increased hepatic fat disposition consistent with hepatic steatosis or "fatty liver" Lilly and Rader, 2007;Miyazaki et al, 2007;Hussain and Bakillah, 2008). The clinical development of molecules that inhibited hepatic MTP was essentially discontinued with respect to use across broad indications.…”