NK1 (neurokinin) receptor
Maropitant Citrate targets the neurokinin-1 (NK1) receptor. Substance P is a neuropeptide that binds to the NK1 receptor in the brainstem's emetic center and the gastrointestinal tract, triggering the vomiting reflex. By acting as a potent and selective antagonist at this receptor, Maropitant blocks the action of substance P, thereby preventing and treating nausea and vomiting. Its high selectivity for the NK1 receptor is a key feature of its mechanism.

In vitro, Maropitant Citrate is characterized by its potent and selective antagonism of the NK1 receptor. Its activity can be assessed in receptor binding assays, where it competes with a labeled ligand for binding to the NK1 receptor. Functional assays, such as measuring its ability to inhibit substance P-induced calcium mobilization or other signaling events, are used to confirm its antagonist activity.

Mice treated with 1 mg/kg Maropitant citrate have much smaller ulcerative dermatitis (UD) lesions. Intravenous maropitant reduces MAC by sixteen percent. By contrast, the MAC (2.17% and 1.92%, respectively) remains unchanged following the epidural injection of either saline or Maropitant. All dogs in S vomited (6/9), retched (1/9) or displayed signs of nausea (2/9). None (0/9) of the dogs in M vomited, retched or displayed signs of nausea. Dogs in M had significantly fewer incidences of vomiting (p=0.0090), vomiting and retching (p=0.0023) and vomiting, retching and nausea (p<0.0001) when compared to S. Conclusion and clinical relevance: Maropitant prevents vomiting, retching and nausea associated with intramuscular hydromorphone administration in dogs. [1]

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The pharmacokinetics of maropitant were evaluated in beagle dogs dosed orally with Cerenia® tablets (Pfizer Animal Health) once daily for 14 consecutive days at either 2 mg/kg or 8 mg/kg bodyweight. Noncompartmental pharmacokinetic analysis was performed on the plasma concentration data to measure the AUC(0-24) (after first and last doses), Ct (trough concentration-measured 24 h after each dose), Cmax (after first and last doses), tmax (after first and last doses), λz (terminal disposition rate constant; after last dose), t(1/2) (after last dose), and CL/F (oral clearance; after last dose). Maropitant accumulation in plasma was substantially greater after fourteen daily 8 mg/kg doses than after fourteen daily 2 mg/kg doses as reflected in the AUC(0-24) accumulation ratio of 4.81 at 8 mg/kg and 2.46 at 2 mg/kg. This is most likely due to previously identified nonlinear pharmacokinetics of maropitant in which high doses (8 mg/kg) saturate the metabolic clearance mechanisms and delay drug elimination. To determine the time to reach steady-state maropitant plasma levels, a nonlinear model was fit to the least squares (LS) means maropitant Ct values for each treatment group. Based on this model, 90% of steady-state was determined to occur at approximately four doses for daily 2 mg/kg oral dosing and eight doses for daily 8 mg/kg oral dosing.[2]
In vivo, Maropitant Citrate is an effective antiemetic in dogs and cats. It is administered orally or by injection. Its efficacy has been demonstrated in clinical studies for the prevention of vomiting due to various causes, including motion sickness and chemotherapy. Its effects are dose-dependent and related to its antagonism of the NK1 receptor.

In vitro enzyme/receptor binding studies for Maropitant Citrate are performed using radioligand binding assays. In these assays, membrane preparations from cells expressing the NK1 receptor are incubated with a radiolabeled NK1 antagonist and varying concentrations of Maropitant. The displacement of the radioligand is measured to determine its affinity (Ki) for the receptor.

In vitro cellular assays for Maropitant Citrate are used to study its effects on cells expressing the NK1 receptor. Cells are treated with the compound and then stimulated with substance P. Key readouts include the inhibition of downstream signaling, such as calcium mobilization or cAMP modulation. These assays confirm its mechanism as a functional NK1 receptor antagonist.

Dogs were admitted to the study if they were greater than 1 year of age, healthy and scheduled to undergo elective orthopedic surgery. Dogs were randomly selected to receive one of two treatments administered by subcutaneous injection. Group M received 1.0 mg kg(-1) of maropitant, Group S received 0.1 mL kg(-1) of saline 1 hour prior to anesthesia premedication. Dogs were premedicated with 0.1 mg kg(-1) of hydromorphone intramuscularly. A blinded observer documented the presence of vomiting, retching and/or signs of nausea for 30 minutes after premedication. [1]

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Analytical phase [2]
Plasma samples were assayed for maropitant and the major hydroxylated t-butyl metabolite of maropitant (CJ-18,518) using the HPLC-MS/MS method modified to incorporate the UPLC. The results demonstrated acceptable accuracy and precision based on Pfizer Animal Health SOPs (±15%, except at the LLOQ where ±20% is acceptable). In this assay, 400 μL of acetonitrile containing the internal standard (an analogue of maropitant with a formula weight of 454.66) at 5 ng/mL was added to 100 μL of canine plasma samples to precipitate proteins. The samples were vortexed and centrifuged, and 10 μL of the supernatant was transferred to a clean 96-well polypropylene plate containing 790 μL of diluent (50/50 acetonitrile/H20 w/0.1% formic acid). Six μliter of each sample was injected onto a Waters ACQUITY UPLC® system with a Waters ACQUITY BEH C18 (1.7 μm, 2.1 × 50 mm) column. The mobile phase was 90% 5 mm ammonium formate with 0.3% formic acid and 10% (B) acetonitrile with 0.3% formic acid, held for 0.2 min with a gradient shift to 99.9% B over 1.8 min and holding for 2 min, then shifting back to 10% B over 0.1 min and holding for another 0.9 min. The flow rate was 0.6 mL/min over the entire run. Detection was accomplished with an API 4000 MS/MS System (Applied Biosystems, Foster City, CA, USA) in positive electrospray mode monitoring the precursor → product transitions 469 → 177 for maropitant, 485 → 193 for the primary metabolite, and 455 → 163 for the internal standard. Integration of peak chromatograms was performed in Analyst Software (v1.4.2, Applied Biosystems) and raw data imported into Watson LIMS (v7.2.0.03, Thermo Electron Corp., Philadelphia, PA, USA). Linear regression was performed using a weighting factor of 1/concentration2. All calculations were performed in Watson.The analytical range of the assay was 1.00 ng/mL to 1000 ng/mL for both maropitant and the primary metabolite in the first two analytical runs and 1.00 ng/mL to 100 ng/mL in the final run. Quality control samples (matrix samples spiked with a known amount of each analyte) were included at 3 ng/mL, 30 ng/mL, and 800 ng/mL in the first two analytical runs and at 3 ng/mL and 30 ng/mL in the final run. The standard curve for analytical run 3 was truncated to an upper limit of quantitation (ULOQ) of 100 ng/mL due to the highest two standards and high QC not falling within acceptable limits. This did not affect the sample results because analytical run 3 contained only a single re-assay sample with a value near the lower range of the standard curve. Samples in the 8 mg/kg treatment group, which were expected to be at or near the ULOQ, were tested after a fivefold dilution with blank plasma. Appropriate dilution QCs were included in the analytical run, and all samples were analyzed in three runs. The inter-run QC bias for maropitant ranged from −5.0% to −2.7% with a maximum coefficient of variation of 5.2% and from −7.0% to −5.0% bias for the metabolite with a maximum coefficient of variation of 6.2%. In dog plasma, the stability of maropitant and its metabolite have been demonstrated for 182 days and 181 days, respectively, when stored at −20°C and for at least 24 h when stored at room temperature (internal data).Pharmacokinetic phase [2]
The pharmacokinetic parameters were estimated using noncompartmental techniques in Watson (v7.2.0.03) using nominal sampling times and doses. Estimates of the area under the plasma concentration vs. time profile (AUC) were determined via trapezoidal summation. The following estimates of the pharmacokinetic parameters for maropitant and the metabolite were determined for each animal for the specified doses:Ct at 24 h after each dose; [2]
Cmax, tmax, AUC0–24 after the first and last dose; [2]
λz (terminal disposition rate constant), CL/F (oral clearance—for maropitant only) and t1/2 (elimination half-life) after the last dose.The λz and t1/2 were estimated from the slope of the terminal portion of the concentration–time curve estimated using linear regression of the log-transformed data. The CL/F was determined by dividing the actual dose by the actual AUC0–24. [2]
In vivo animal studies for Maropitant Citrate are conducted in models of emesis, such as those induced by apomorphine or motion sickness. Animals are treated with the compound, and the prevention of vomiting is measured. These studies confirm its efficacy as an antiemetic.

Maropitant plasma concentration LS means, with upper or lower 95% CI as error bars, are shown in Fig. 1 for 2 mg/kg and in Fig. 2 for 8 mg/kg. Least squares means pharmacokinetic variables for the study are listed in Table 1 for maropitant and Table 2 for the primary metabolite. The mean half-life after the last 2 mg/kg dose (9.22 h; Table 1) was significantly (P < 0.01) less than the half-life after the last 8 mg/kg dose (21.7 h; Table 1). The single-dose pharmacokinetics of maropitant have been previously reported (Benchaoui et al., 2007b) and they reported mean half-lives after a 2 mg/kg oral dose in the range of 4.0–7.1 h and 5.5–7.8 h for 8 mg/kg dosed orally. Following the first dose in the current study, the mean half-life in the 8 mg/kg group was 8.1 h, although this is not directly comparable to the day 14 half-life because it is calculated only until 24 h, it does appear that an increase in half-life from first to last dose is evident. These results indicate that this difference in half-lives was not demonstrated after a single dose and suggests that with multiple dosing at the 8 mg/kg level, a metabolic elimination pathway may become saturated delaying drug elimination (Benchaoui et al., 2007b). [2]

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For maropitant dosed at 2 mg/kg, the accumulation ratio (95% CI) was 2.46 (1.68, 3.61) for AUC0–24 and 2.03 (1.46, 2.81) for Cmax. At that same dosage, the primary metabolite showed accumulation ratios of 2.06 (1.43, 2.97) and 1.26 (0.986, 1.61) for the AUC0–24 and Cmax, respectively. The maropitant accumulation ratio for animals dosed at 8 mg/kg was 4.81 (3.28, 7.05) for AUC0–24 and 2.77 (1.99, 3.84) for Cmax. The primary metabolite showed accumulation ratios of 2.42 (1.68, 3.49) and 1.45 (1.13 1.85) for the AUC0–24 and Cmax, respectively, at 8 mg/kg. The single-dose PK results (Benchaoui et al., 2007b) would suggest that the accumulation between 2 mg/kg and 8 mg/kg would be similar; however, these results indicate that at 8 mg/kg the total exposure (AUC0–24) accumulated at nearly twice the rate than at 2 mg/kg. This supports that a metabolic elimination pathway may have become saturated after repeated 8 mg/kg dosing. Results – time to steady-state The LS means maropitant Ct values were fit to the model described above. Abnormally high maropitant Ct values were noted in six of the eight dogs after the second dose for the 2 mg/kg dose group. Upon investigation, only the maropitant concentration values were high for these animals; therefore, it was believed that the values resulted from a sample handling error and were not accurate representations of the actual blood plasma concentration in the animals. As both analytes were assayed from the same standard solution in the same run, the metabolite would have also yielded an erroneous result if the error was analytical in nature. A source for contamination could have been from the dose solution during sample collection. Therefore, the Ct values for that time point were excluded from the model fitting. The model fits the maropitant LS means data quite well (Fig. 3) and parameters are reported in Table 3. The model estimates that the average number of Cerenia doses required to reach 90% of steady-state (D90) was 4.30 at 2 mg/kg and 8.09 at 8 mg/kg. [2]
Pharmacokinetic properties of Maropitant Citrate include good oral bioavailability in dogs and cats. It has a long half-life, supporting once-daily dosing. It is metabolized in the liver. Its citrate salt form enhances its stability and solubility.

Maropitant Citrate is generally well-tolerated at therapeutic doses. Common side effects in animals may include mild gastrointestinal upset. It is contraindicated in animals with known hypersensitivity. Specific toxicity data are available from its veterinary use.

[1]. Efficacy of maropitant in preventing vomiting in dogs premedicated with hydromorphone. Vet Anaesth Analg. 2013 Jan;40(1):28-34.

[2]. The pharmacokinetics of maropitant citrate dosed orally to dogs at 2 mg/kg and 8 mg/kg once daily for 14 days consecutive days. J Vet Pharmacol Ther. 2013 Oct;36(5):462-70.

[3]. Effect of epidural and intravenous use of the neurokinin-1 (NK-1) receptor antagonist maropitant on the sevoflurane minimum alveolar concentration (MAC) in dogs. Vet Anaesth Analg. 2012 Mar;39(2):201-5.

[4]. Safety and efficacy of injectable and oral maropitant, a selective neurokinin 1 receptor antagonist, in a randomized clinical trial for treatment of vomiting in dogs. J Vet Pharmacol Ther. 2008 Dec;31(6):538-43.

[5]. The pharmacokinetics of maropitant, a novel neurokinin type-1 receptor antagonist, in dogs. J Vet Pharmacol Ther. 2007 Aug;30(4):336-44.

Maropitant citrate is a neurokinin receptor antagonist with antiemetic effects. This product is approved for veterinary use only.
See also: Maropitant (containing the active ingredient).
Indications
Tablets (dogs): For the prevention of chemotherapy-induced nausea. For the prevention of vomiting caused by motion sickness. For the prevention and treatment of vomiting in combination with celeriac solution for injection and other adjunctive therapies. Injectable solution (dogs): For the treatment and prevention of chemotherapy-induced nausea. For the prevention of vomiting other than that caused by motion sickness. For the treatment of vomiting in combination with other adjunctive therapies. For the prevention of perioperative nausea and vomiting, and to improve recovery from general anesthesia following the use of the alpha-opioid receptor agonist morphine. Cats: For the prevention of vomiting and relief of nausea, except that caused by motion sickness. For the treatment of vomiting, in combination with other adjunctive therapies.
Maropitant Citrate is a veterinary drug used as an antiemetic. It is marketed under the brand name Cerenia. It is a highly selective NK1 receptor antagonist. Its development represented a significant advance in veterinary medicine for the management of nausea and vomiting in companion animals.

C32H40N2O.C6H8O7.H2O

678.8116

300.175

C, 67.24; H, 7.42; N, 4.13; O, 21.21

359875-09-5

Maropitant-13C,d3; 359875-09-5 (citrate hydrate); 147116-67-4; 862543-54-2 (citrate)

204107

White to off-white solid

572.6ºC at 760 mmHg

153-159ºC(lit.)

300.1ºC

2.924

6

11

13

49

848

2

O.OC(CC(C(=O)O)(O)CC(=O)O)=O.COC1C=CC(C(C)(C)C)=CC=1CN[C@H]1C2CCN(CC2)[C@@H]1C(C1C=CC=CC=1)C1C=CC=CC=1

PGVSXRHFXJOMGW-YBZGWEFGSA-N

InChI=1S/C32H40N2O.C6H8O7.H2O/c1-32(2,3)27-15-16-28(35-4)26(21-27)22-33-30-25-17-19-34(20-18-25)31(30)29(23-11-7-5-8-12-23)24-13-9-6-10-14-24;7-3(8)1-6(13,5(11)12)2-4(9)10;/h5-16,21,25,29-31,33H,17-20,22H2,1-4H3;13H,1-2H2,(H,7,8)(H,9,10)(H,11,12);1H2/t30-,31-;;/m0../s1

(2S,3S)-2-benzhydryl-N-[(5-tert-butyl-2-methoxyphenyl)methyl]-1-azabicyclo[2.2.2]octan-3-amine;2-hydroxypropane-1,2,3-tricarboxylic acid;hydrate

Maropitant citrate monohydrate; 359875-09-5; Maropitant citrate hydrate; Cerenia; CJ-11,972;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO: ~100 mg/mL (~147.3 mM; with ultrasonication)
H2O: ~5 mg/mL (~7.4 mM; with ultrasonication and warming by heating to 60°C)

Solubility in Formulation 1: ≥ 2.5 mg/mL (3.68 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), Clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of DMSO stock solution (25.0 mg/mL) to 900 μL of 20% SBE-β-CD saline and mix well.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (3.68 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), Clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of DMSO stock solution (25.0 mg/mL) to 900 μL of corn oil and mix well.

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 (Please use freshly prepared in vivo formulations for optimal results.)