Dirlotapide (CP742033)
(Synonyms: CP742033; Slentrol) 目录号 : GC31454Dirlotapide (CP742033) (CP742033) 是一种肠道选择性微粒体甘油三酯转移蛋白 (MTP) 抑制剂,可有效减轻肥胖犬的体重。
Cas No.:481658-94-0
Sample solution is provided at 25 µL, 10mM.
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Animal experiment: | Dirlotapide in the commercial formulation of a 5-mg/mL oil solution, is administered at an initial rate of 0.5 mg/kg adjusted individually based on the weight loss change in the previous 2 weeks. Dogs assigned to placebo receive the oil vehicle (identical in appearance to the dirlotapide solution) at a rate of 0.1 mL/kg and 0.075 mL/kg during the weight loss and weight management phases, respectively. The dose volume is administered directly into the dog's mouth with a dosing syringe approximately 30 min before feeding. |
References: [1]. Kirk CA, et al. Influence of dirlotapide, a microsomal triglyceride transfer protein inhibitor, on the digestibility of a dry expanded diet in adult dogs. J Vet Pharmacol Ther. 2007 Aug;30 Suppl 1:66-72. |
Dirlotapide (CP742033) is a gut-selective inhibitor of microsomal triglyceride transfer protein (MTP) that reliably produces weight loss in obese dogs.
Dogs receiving 0.3 mg dirlotapide/kg once daily have a small but significant (P=0.018) decrease (6.16 ± 2.22%, mean ± SD) in crude fat digestibility compared with the placebo-treated food-restricted dogs, but no difference in crude protein, dry matter, or energy digestibility is observed. Dirlotapide effectively reduces appetite and energy intake without affecting nutrient digestibility, except for a minimal decrease in fat digestibility[1]. Dirlotapide (0.5 mg/kg) results in a high rate of weight loss (3.3% weekly) and anorexia, emesis, and loose stools for some dogs. Dirlotapide produces weight loss by both reducing appetite (about 90% of the weight loss activity) and by increasing fecal fat excretion (about 10% of the weight loss activity)[2].
[1]. Kirk CA, et al. Influence of dirlotapide, a microsomal triglyceride transfer protein inhibitor, on the digestibility of a dry expanded diet in adult dogs. J Vet Pharmacol Ther. 2007 Aug;30 Suppl 1:66-72. [2]. Wren JA, et al. Biologic activity of dirlotapide, a novel microsomal triglyceride transfer protein inhibitor, for weight loss in obese dogs. J Vet Pharmacol Ther. 2007 Aug;30 Suppl 1:33-42.
Cas No. | 481658-94-0 | SDF | |
别名 | CP742033; Slentrol | ||
Canonical SMILES | O=C(C(N1C)=CC2=C1C=CC(NC(C3=CC=CC=C3C4=CC=C(C(F)(F)F)C=C4)=O)=C2)N[C@@H](C5=CC=CC=C5)C(N(C)CC6=CC=CC=C6)=O | ||
分子式 | C40H33F3N4O3 | 分子量 | 674.71 |
溶解度 | Soluble in DMSO | 储存条件 | Store at -20°C |
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1 mg | 5 mg | 10 mg | |
1 mM | 1.4821 mL | 7.4106 mL | 14.8212 mL |
5 mM | 0.2964 mL | 1.4821 mL | 2.9642 mL |
10 mM | 0.1482 mL | 0.7411 mL | 1.4821 mL |
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Dirlotapide: a review of its properties and role in the management of obesity in dogs
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.
The safety of dirlotapide in dogs
The safety of dirlotapide in dogs was evaluated in two studies with parallel designs. In an acute tolerance study, 24 beagles (six dogs per treatment) were treated orally once daily for 14 days with placebo or dirlotapide at 2.5, 5.0, or 10.0 mg/kg/day. In a margin-of-safety study, 38 overweight, neutered beagles were treated orally once daily for 3 months with dirlotapide at doses up to 0.5 mg/kg/day (six dogs), 1.5 mg/kg/day (12 dogs) and 2.5 mg/kg/day (six dogs). Control dogs received placebo at 0.3 mL/kg/day (10 dogs) and 0.5 mL/kg/day (four dogs). Results were similar for both studies, and no serious adverse events were observed. Dirlotapide was clinically well-tolerated in dogs at dosages up to 10 mg/kg/day for 14 days and 2.5 mg/kg/day for 3 months. Dirlotapide produced the expected decrease in food intake and body weight (up to 20-40%) without ill effects. Clinical, pathologic, and histopathologic findings were reversible and consistent with suppression of food intake and rapid weight loss produced by elevated dirlotapide dosages. In both studies, sporadic emesis and loose stools were observed in both placebo and dirlotapide-treated dogs. Incidence of emesis generally increased with dose and decreased with treatment time. Elevations in hepatic transaminase activity were seen in dogs treated with more than 1.5 mg/kg dirlotapide daily, but were not associated with clinical signs or microscopic evidence of hepatic degeneration or necrosis.
Dirlotapide, a U.S. Food and Drug Administration-approved first-in-class obesity drug for dogs-will humans be next?
Evaluation of dirlotapide for sustained weight loss in overweight Labrador retrievers
The effects of dirlotapide on body weight (BW) reduction were investigated in overweight Labradors in two parallel-design studies. Study A involved 42 dogs randomized to 0.0, 0.025, 0.05, 0.1, 0.2 or 0.4 mg dirlotapide/kg/day orally for 4 weeks. Study B involved 72 dogs randomized to nine treatments: placebo (24 weeks); dirlotapide (24 weeks) followed by placebo (28 weeks); or dirlotapide (52 weeks); on diets containing 5%, 10% or 15% fat. Dirlotapide dose (initially 0.1 mg/kg) was adjusted monthly during 24-week weight-loss and subsequent 28-week weight-stabilization phases. Food was offered above maintenance energy requirements (MERx 1.1-1.2) based on initial BW. Body composition (body fat, lean tissue and bone mineral content) was monitored using dual-energy X-ray absorptiometry. After treatment, dogs that had received dirlotapide for 52 weeks were fed 90% of quantity consumed at week 52. In study A, BW and food intake decreased asymptotically with dose: mean weekly weight loss exceeded 1% at 0.1-0.4 mg/kg. In study B, dirlotapide resulted in significant mean weekly weight loss (>0.8%) and decreased food intake over 24 weeks compared with placebo (P = 0.0001) for all diets. Food restriction minimized post-treatment weight rebound. Dirlotapide administered daily to dogs for up to 52 weeks was clinically safe and resulted in sustained weight reduction.
Pharmacokinetics of dirlotapide in the dog
An overview of the pharmacokinetics of dirlotapide in beagle dogs is presented. The following mean parameters were observed after a 0.3-mg/kg i.v. dose of dirlotapide: plasma clearance of 7.8 mL/min/kg and volume of distribution of 1.3 L/kg. Following single oral doses of 0.05, 0.3, and 1.0 mg/kg to fed dogs and 0.3 mg/kg to fasted dogs using the commercial formulation, mean C(max) of 7.5, 46, 97, and 31 ng/mL, respectively, were observed at mean t(max) of 0.8-2.0 h. AUC and C(max) increased with increasing dose, but not proportionally. Oral bioavailability was 22-41%. Exposure, as reflected by AUC, was 54% higher in the fed than fasted state. In a 14-day repeated-dose study (0.3 mg/kg dose), the mean accumulation ratio was 3.7. In a 3-month study at doses of 0.4-2.5 mg/kg, accumulation ratios ranged from 2.0 to 6.7 at day 29 and from 1.3 to 4.1 at day 87. In summary, dirlotapide exhibited low clearance, low first-pass metabolism, moderate volume of distribution, low-to-moderate oral bioavailability, a modest food effect, and variable accumulation. Large interanimal variability in systemic exposure was noted for all routes and doses, but there were no consistent sex differences.