NK1/neurokinin receptor
Maropitant is a selective neurokinin (NK1) receptor antagonist. It functions by preventing substance P from binding to the chemoreceptor trigger zone (CRTZ) and the emetic center. Substance P is a neuropeptide that plays a key role in the emetic reflex. By blocking the NK1 receptor, Maropitant inhibits the emetic response and prevents vomiting. The compound is a synthetic, non-peptide neurokinin-1 (NK1) receptor antagonist that inhibits substance P. It also exhibits antiviral activity against SARS-CoV-2.

In vitro, Maropitant significantly reduces the size of ulcerative dermatitis (UD) lesions in mice. It exhibits antiviral activity against SARS-CoV-2, demonstrating its potential across several assays and cell lines. Its in vitro activity is characterized by potent NK1 receptor antagonism and antiviral effects. Maropitant's ability to block substance P binding contributes to its antiemetic and potential anti-inflammatory effects.

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 is a selective and orally active neurokinin (NK1) receptor antagonist that is highly effective in preventing vomiting. It was created by Zoetis expressly to treat motion sickness and vomiting in dogs. The compound acts by blocking the binding of substance P within the emetic center and the chemoreceptor trigger zone (CRTZ). Its in vivo efficacy as an antiemetic is well-established in veterinary medicine. Maropitant also exhibits antiviral activity against SARS-CoV-2 in vitro.

In vitro enzyme/receptor binding assays for Maropitant typically involve measuring its binding affinity to the neurokinin (NK1) receptor. Radioligand binding assays using membrane preparations expressing the NK1 receptor are performed to determine the binding affinity. These assays confirm the compound's mechanism of action as an NK1 receptor antagonist. The compound's selectivity for NK1 over other neurokinin receptors can also be assessed.

In vitro cellular assays for Maropitant typically involve measuring its ability to inhibit substance P-induced signaling in cells expressing the NK1 receptor. The compound blocks substance P binding and inhibits downstream signaling. These cell-based studies demonstrate the compound's functional antagonism at the NK1 receptor. Maropitant's antiviral activity against SARS-CoV-2 can also be assessed in cell-based antiviral assays.

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 models for Maropitant typically involve models of vomiting induced by various stimuli, such as motion sickness or chemotherapy agents. The compound is administered orally, and the emetic response is assessed. Maropitant is highly effective in preventing vomiting in these models. Its efficacy in dogs is well-established. Doses and administration routes are optimized based on the specific model and experimental endpoints. These studies provide evidence for the compound's in vivo antiemetic efficacy.

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]
Maropitant has a molecular weight of 468.67 g/mol. It is a synthetic, non-peptide neurokinin-1 (NK1) receptor antagonist. The compound is typically stored under appropriate conditions to maintain stability. Its physicochemical properties support its use in both in vitro and in vivo studies. Maropitant's solubility and formulation for administration should be optimized based on specific experimental requirements. The compound is an orally active antiemetic used in veterinary medicine.

Maropitant is a well-tolerated antiemetic with a favorable safety profile in veterinary medicine. Common adverse effects may include sedation, diarrhea, and anorexia. The compound should be used with caution in patients with hepatic impairment. Its safety profile is well-established from clinical use in dogs. Maropitant is for research use only and is not approved for human therapeutic use. It represents a valuable tool for studying NK1 receptor biology and emesis.

[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 (used in the form of Maropitant citrate) is a neurokinin receptor antagonist developed by Zoetis specifically for the treatment of motion sickness and vomiting in dogs. It was approved by the U.S. Food and Drug Administration (FDA) for dogs in 2007 and has recently been approved for cats as well.
See also: Maropitant citrate (salt form) Anhydrous Maropitant citrate (the active ingredient).
Indications
Dogs: For the treatment and prevention of chemotherapy-induced nausea; for the prevention of vomiting excluding motion sickness; for the treatment of vomiting, in combination with other adjunctive therapies; for the prevention of perioperative nausea and vomiting, and for improving 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 for nausea caused by motion sickness; for the treatment of vomiting, in combination with other adjunctive therapies.
Tablets for 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 other adjunctive therapies, and in combination with celeriac solution for injection. Injectable solution for dogs: For the treatment and prevention of chemotherapy-induced nausea. For the prevention of vomiting (excluding vomiting 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. For cats: For the prevention of vomiting and relief of nausea (excluding nausea caused by motion sickness). For the treatment of vomiting, in combination with other adjunctive therapies.
Maropitant (CAS# 147116-67-4), also known as CJ-11972, is a selective and orally active neurokinin (NK1) receptor antagonist. It acts by blocking the binding of substance P within the emetic center and the chemoreceptor trigger zone (CRTZ). Maropitant is highly effective in preventing vomiting and was developed by Zoetis specifically to treat motion sickness and vomiting in dogs. It also exhibits antiviral activity against SARS-CoV-2. The compound is for research use only and is not approved for human therapeutic use.

C32H40N2O

468.6728

468.314

C, 82.01; H, 8.60; N, 5.98; O, 3.41

147116-67-4

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

204108

White solid powder

6.706

1

3

8

35

620

2

CC(C)(C)C1=CC=C(OC)C(CN[C@@H]2[C@H](C(C3=CC=CC=C3)C4=CC=CC=C4)N5CCC2CC5)=C1

OMPCVMLFFSQFIX-CONSDPRKSA-N

InChI=1S/C32H40N2O/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/h5-16,21,25,29-31,33H,17-20,22H2,1-4H3/t30-,31-/m0/s1

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

Maropitant; CJ-11972; CJ 11972; CJ11972; CJ-11,972; CJ 11,972; CJ11,972; brand name: Cerenia

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

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

DMSO: ~25 mg/mL (~53.3 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (5.33 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 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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