Maropitant's pharmacokinetics and pharmacology

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Sep 01, 2009

Pharmacokinetics

Maropitant is a weak base, is highly lipophilic, and belongs to the quinuclidine class.1,2 Three essential elements in the quinidine structure are important for the interactivity of a ligand with the NK1 receptor: the bridgehead basic nitrogen, the benzhydryl moiety, and the 2-methoxybenzyl amino side chain.

After oral administration, maropitant is absorbed through the intestinal tract and is a substrate for efflux via the surface membrane by the multidrug transporter P-glycoprotein.3 P-glycoprotein actively secretes the absorbed drug back into the intestinal lumen, decreasing drug bioavailability. Maximum plasma concentrations occur 0.75 hours after subcutaneous administration at 1 mg/kg, and 1.7 and 1.9 hours after oral administration of 8 and 2 mg/kg doses, respectively.4 In dogs, the absolute bioavailability of maropitant is markedly higher (90.7%) after subcutaneous administration (1 mg/kg) than after oral administration (23.7% at the 2-mg/kg dose and 37% at the 8-mg/kg dose).4 In cats, the bioavailability is 117% and 50% when administered subcutaneously and orally, respectively.5 Maropitant's subcutaneous bioavailability may be underestimated because of nonlinear pharmacokinetics at therapeutic doses.5 Feeding status does not significantly affect oral bioavailability.1,6

In blood, plasma protein binding is high (> 99%).6 Thus, closely monitor dogs with hypoproteinemia that are receiving maropitant; lower dosages of maropitant could be used in these patients. Maropitant, a lipophilic compound, crosses the blood-brain barrier. In gerbils, the mean brain:plasma concentration ratio eight hours after subcutaneous injection of 1 mg/kg is 3.59.7 Adverse effects reported may include ataxia.1 The hepatic metabolism of maropitant involves two cytochrome P450 isoenzymes in dogs: CYP3A12 (high capacity, low affinity) and CYP2D15 (low capacity, high affinity).1,4 Twenty-one metabolites have been identified.1 The principal metabolite is a pharmacologically active product of hydroxylation.1,4

The drug is eliminated by hepatic clearance. The apparent elimination half-life in dogs is 7.75 hours after subcutaneous dosing at 1 mg/kg and 4.03 hours after one oral dose at 2 mg/kg.4 An accumulation ratio (when multiple doses are given, the drug accumulates until the plasma concentration is large enough for elimination to balance absorption) of 1.5 occurs after once-daily use for five consecutive days at 1 mg/kg given subcutaneously or 2 mg/kg given orally.1,4 The accumulation ratio is 2.18 after two consecutive days at 8 mg/kg given orally daily.1,4 Maropitant is distributed into milk in dogs but has not been measured quantitatively.2

Pharmacology

Maropitant is a highly selective neurokinin 1 (NK1) receptor antagonist that blocks the action of substance P, a key neurotransmitter involved in emesis, in the central nervous system.1 Substance P (neurokinin 1), a neuropeptide composed of 11 amino acids, belongs to the tachykinin family (biologically active neuropeptides that have pharmacologic effects on the cardiovascular, genitourinary, respiratory, gastrointestinal, and central nervous systems and in glandular tissue) and is found in high concentrations in the emetic center (area postrema, nucleus tractus solitarius, and dorsal motor nucleus of the vagus).8 Substance P's action is mediated by three G protein-coupled receptors designated NK1, NK2, and NK3.8 Most of substance P's central and peripheral effects are mediated by NK1 receptors.8 The NK1 receptor can be found in both the central and peripheral nervous system. It is also present in the brainstem, neurons, vascular endothelial cells, gastrointestinal tract, pulmonary tissue, and muscle.9 Substance P is the preferred ligand for the NK1 receptor, the predominant tachykinin receptor in the brain.8

Maropitant mimics substance P's structure and binds the NK1 receptors so they cannot bind substance P, thus decreasing stimulation of the emetic center. By inhibiting substance P binding, maropitant suppresses both central and peripheral causes of emesis and the effects of a variety of emetics10 such as apomorphine, xylazine, ipecac syrup, and cisplatin in dogs, as well as xylazine in cats.5 Maropitant at an oral dose of 2 mg/kg will inhibit emesis induced by apomorphine (0.01 mg/kg intravenously) in dogs.11 The substance P-NK1 receptor complex is the final common pathway of the vomiting reflex, which may explain why maropitant has a broader spectrum of antiemetic activity than 5-HT3 serotoninergic antagonists (ondansetron, dolasetron), D2-dopaminergic antagonists (metoclopramide), M1 cholinergic antagonists (prochlorperazine), and glucocorticoids (dexamethasone).12 Recent studies have shown that NK1 receptor antagonists may also help treat depression and anxiety in people.8,13 Other potential indications of the NK1 receptor antagonists in people include asthma, neural injury, and stroke.12

Lotfi El Bahri, DVM, MSc, PhD
Department of Pharmacology and Toxicology
École Nationale de Médecine Vétérinaire
2020 Sidi-Thabet, Tunisia