Dirlotapide: a review of its properties and role in the management of obesity in dogs

Abstract

Dirlotapide is a microsomal triglyceride transfer protein (MTP) inhibitor developed specifically for canine weight reduction. MTP catalyzes the assembly of triglyceride-rich apolipoprotein-B containing lipoproteins to form chylomicrons in the intestinal mucosa and very low-density lipoproteins in the liver. Following oral administration, dirlotapide has in vivo selectivity for intestinal MTP compared with hepatic MTP. In addition to reducing intestinal fat absorption, dirlotapide also reduces food intake in a dose-dependent manner, probably via increased release of peptide YY into the circulation. The decrease in food intake is responsible for the majority of the weight reduction effect. In clinical use, it is recommended to adjust the dose according to the observed weight loss of each individual. The initial dose of 0.05 mg/kg is doubled after 14 days and then adjusted monthly, the maximum permitted daily dose is 1.0 mg/kg, although doses as high as 10 mg/kg have been administered to dogs without severe adverse experience in safety studies. Dirlotapide can be used without necessitating changes to the current feeding or exercise regimens, but it is desirable to monitor the food intake during weight-stabilization to establish revised feeding and exercise routines that will minimize the risk of weight regain post-treatment. The drug offers a novel approach that is applicable in cases where dietary management alone has proved to be unsuccessful.

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

“…In addition, SLx-4090 decreased the body weight gain in ApoE(Ϫ/Ϫ) mice over the course of treatment and had a positive impact on liver and fat stores as evidenced by reductions in fat and liver weight to body weight ratios. The overall reduction in body weight compared with vehicle animals was not the result of a decrease in food intake that has been reported for the MTP inhibitor dirlotapide (Wren et al, 2007). The enterocytic selectivity of SLx-4090 was further supported by the lack of elevation of the liver transaminases even at the highest dose tested.…”

“…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).…”

Dietary fat sensing via fatty acid oxidation in enterocytes: possible role in the control of eating

“…Pharmacologic inhibition of chylomicron release antagonizes the otherwise strong, eating-inhibitory effect of intraintestinal fat administration under some conditions (139), and this effect may be due to blockade of apolipoprotein AIV formation (139). In contrast, pharmacologic interference with enterocyte TAG synthesis or chylomicron assembly generally inhibits eating (15,170), and some evidence suggests that the eating-inhibitory effect of TAG synthesis blockade may be related to a metabolic shift from TAG synthesis to FAO. In our hands, DGAT1 inhibition failed to reduce food intake when rats were fed regular chow but clearly inhibited eating when rats were fed a high-fat diet, and this effect was accompanied by a metabolic shift from TAG synthesis to FAO (143).…”

JTT-130, a Novel Intestine-Specific Inhibitor of Microsomal Triglyceride Transfer Protein, Suppresses Food Intake and Gastric Emptying with the Elevation of Plasma Peptide YY and Glucagon-Like Peptide-1 in a Dietary Fat-Dependent Manner

“…In addition, recent studies have demonstrated that inhibition of intestinal MTP results in suppression of food intake, accompanied by increased circulating levels of gut peptides such as PYY (Wren et al, 2007). In this study, we examined the effects of JTT-130, an intestine-specific MTP inhibitor, on food intake in Sprague-Dawley rats.…”