Pharmacokinetics of ezlopitant, a novel non-peptidic neurokinin-1 receptor antagonist in preclinical species and metabolite kinetics of the pharmacologically active metabolites

Reed-Hagen, Anne E.; Tsuchiya, Megumi; Shimada, Kaoru; Wentland, Joann; Obach, R. Scott

doi:10.1002/1099-081x(199912)20:9<429::aid-bdd209>3.0.co;2-d

Cited by 16 publications

(10 citation statements)

References 8 publications

(2 reference statements)

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“…To further elucidate the role of the NK1-receptor system in the regulation of consumption of natural reinforcers and ethanol, we evaluated the efficacy of a clinically safe and selective NK1-receptor antagonist, ezlopitant (CJ-11,974) [38], [39] to decrease sucrose and ethanol consumption and seeking. Ezlopitant has previously been investigated in clinical trials as a potential therapy for pain, chemotherapy-induced emesis and irritable bowel syndrome [40], [41]. The present study gives further support to the hypothesis that the NK1-receptor system might be a novel therapeutic target for addictive disorders.…”

Section: Introductionsupporting

confidence: 82%

The Neurokinin 1 Receptor Antagonist, Ezlopitant, Reduces Appetitive Responding for Sucrose and Ethanol

et al. 2010

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BackgroundThe current obesity epidemic is thought to be partly driven by over-consumption of sugar-sweetened diets and soft drinks. Loss-of-control over eating and addiction to drugs of abuse share overlapping brain mechanisms including changes in motivational drive, such that stimuli that are often no longer ‘liked’ are still intensely ‘wanted’ [7], . The neurokinin 1 (NK1) receptor system has been implicated in both learned appetitive behaviors and addiction to alcohol and opioids; however, its role in natural reward seeking remains unknown.Methodology/Principal FindingsWe sought to determine whether the NK1-receptor system plays a role in the reinforcing properties of sucrose using a novel selective and clinically safe NK1-receptor antagonist, ezlopitant (CJ-11,974), in three animal models of sucrose consumption and seeking. Furthermore, we compared the effect of ezlopitant on ethanol consumption and seeking in rodents. The NK1-receptor antagonist, ezlopitant decreased appetitive responding for sucrose more potently than for ethanol using an operant self-administration protocol without affecting general locomotor activity. To further evaluate the selectivity of the NK1-receptor antagonist in decreasing consumption of sweetened solutions, we compared the effects of ezlopitant on water, saccharin-, and sodium chloride (NaCl) solution consumption. Ezlopitant decreased intake of saccharin but had no effect on water or salty solution consumption.Conclusions/SignificanceThe present study indicates that the NK1-receptor may be a part of a common pathway regulating the self-administration, motivational and reinforcing aspects of sweetened solutions, regardless of caloric value, and those of substances of abuse. Additionally, these results indicate that the NK1-receptor system may serve as a therapeutic target for obesity induced by over-consumption of natural reinforcers.

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Section: Introductionsupporting

confidence: 82%

The Neurokinin 1 Receptor Antagonist, Ezlopitant, Reduces Appetitive Responding for Sucrose and Ethanol

et al. 2010

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“…Serum and Brain Tissue Binding Studies. The binding of CP-615,003 and CP-900,725 in pooled rat or dog serum (at 20 -2000 ng/ml CP-615,003 and 10 -1000 ng/ml CP-900,725), ex vivo protein binding samples from the clinical study, and 20% rat brain homogenate (100 ng/ml CP-615,003 or CP-900,725) prepared in Dulbecco's phosphate-buffered saline (pH 7.4) were determined by equilibrium dialysis as described previously (Reed-Hagen et al, 1999). Bioanalysis of CP-615,003 and CP-900,725 in dialysate and retentate samples was performed using the LC/MS/MS method described later.…”

Section: Methodsmentioning

confidence: 99%

Central Nervous System Pharmacokinetics of the Mdr1 P-Glycoprotein Substrate CP-615,003: Intersite Differences and Implications for Human Receptor Occupancy Projections from Cerebrospinal Fluid Exposures

Venkatakrishnan¹,

Tseng²,

Nelson³

et al. 2007

Drug Metab Dispos

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ABSTRACT:The central nervous system (CNS) distribution and transport mechanisms of the investigational drug candidate CP-615,003 (N-[3-fluoro-4-[2-(propylamino)ethoxy]phenyl]-4,5,6,7-tetrahydro-4-oxo-1H-indole-3-carboxamide) and its active metabolite CP-900,725 have been characterized. Brain distribution of CP-615,003 and CP-900,725 was low in rats and mice (brain-to-serum ratio < 0.2). Cerebrospinal fluid (CSF)-to-serum ratios of CP-615,003 were 6-to 8-fold lower than the plasma unbound fraction in rats and dogs. In vitro, CP-615,003 displayed quinidine-like efflux in MDR1-expressing Madin-Darby canine kidney II cells. The brain-to-serum ratio of CP-615,003 in mdr1a/1b (؊/؊) mice was ϳ7 times that in their wild-type counterparts, confirming that impaired CNS distribution was explained by P-gp efflux transport. In contrast, P-gp efflux did not explain the impaired CNS penetration of CP-900,725. Intracerebral microdialysis was used to characterize rat brain extracellular fluid (ECF) distribution. Interestingly, the ECF-to-serum ratio of the P-gp substrate CP-615,003 was 7-fold below the CSF-toserum ratio, whereas this disequilibrium was not observed for CP-900,725. In a clinical study, steady-state CSF exposures were measured after administration of 100 mg of CP-615,003 b.i.d. The human CSF-to-plasma ratios of CP-615,003 and CP-900,725 were both ϳ10-fold below their ex vivo plasma unbound fractions, confirming impaired human CNS penetration. Preliminary estimates of CNS receptor occupancy from human CSF concentrations were sensitive to assumptions regarding the magnitude of the CSF-ECF gradient for CP-615,003 in humans. In summary, this case provides an example of intersite differences in CNS pharmacokinetics of a P-gp substrate and potential implications for projection of human CNS receptor occupancy of transporter substrates from CSF pharmacokinetic data when direct imaging-based approaches are not feasible.The investigational psychopharmacologic drug candidate CP-615,003 (N-[3-fluoro-4-[2-(propylamino)ethoxy]phenyl]-4,5,6,7-tetrahydro-4-oxo-1H-indole-3-carboxamide, Fig. 1A) is a potent subtype-selective partial agonist at the GABA A receptor complex (binding K i 1.1 nM). In rats, the biotransformation of CP-615,003 is mainly characterized by the formation of hydroxylated metabolites (Shaffer et al., 2005). However, in the monkey and in humans, oxidative deamination is the primary route of metabolism resulting in the formation of a circulating metabolite CP-900,725 (Shaffer et al., 2005; Fig. 1B), which is pharmacologically active (target receptor binding K i 1.9 nM).Tissue distribution studies conducted during early clinical development of CP-615,003 suggested limited brain penetration, with brain-to-plasma total concentration ratios of Ͻ0.2 in rodents. Because assessment of delivery to the central nervous system (CNS) and the role of the blood-brain barrier drug transporter P-glycoprotein is a key component of the discovery and development of drugs intended to be CNS-active (Mahar Doan et al., 2002;Shen et al...

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Section: Introductionmentioning

confidence: 99%

“…It also inhibited SP-induced contraction of guinea pig trachea with a pA 2 value of 7.8, but had no effects on the baseline tension and maximum contractile response. Recent clinical studies have shown that ezlopitant is effective for the treatment of either the acute or delayed phase of emesis associated with antineoplastic treatment using cisplatin, suggesting a role of NK1 receptor antagonists in the clinic for the control of emesis to improve the quality of life of cancer patients undergoing chemotherapy (Hesketh et al, 1999).The pharmacokinetics of ezlopitant in several animal species have been reported and characterized by high clearance values with a moderate to high volume of distribution, a low to moderate terminal half-life, and low bioavailability (Reed-Hagen et al, 1999 …”

mentioning

confidence: 99%

“…The pharmacokinetics of ezlopitant in several animal species have been reported and characterized by high clearance values with a moderate to high volume of distribution, a low to moderate terminal half-life, and low bioavailability (Reed-Hagen et al, 1999). Prelimi-nary in vitro studies using hepatic microsomes from rat, dog, and humans and recombinant human P450 suggested that ezlopitant is metabolized into two active metabolites, and , predominantly by CYP3A4/3A5, and to a lesser extent by CYP2D6 (Obach, 2000(Obach, , 2001.…”

mentioning

confidence: 99%

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Metabolism, Pharmacokinetics, and Excretion of a Nonpeptidic Substance P Receptor Antagonist, Ezlopitant, in Normal Healthy Male Volunteers: Characterization of Polar Metabolites by Chemical Derivatization with Dansyl Chloride

Prakash

O’Donnell²,

Khojasteh-Bakht³

2007

Drug Metab Dispos

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ABSTRACT:The excretion, biotransformation, and pharmacokinetics of ezlopitant [(2-benzhydryl-1-aza-bicyclo[2.2.2]oct-3-yl)-(5-isopropyl-2-methoxy-benzyl)-amine], a substance P receptor antagonist, were investigated in healthy male volunteers after oral administration of a single 200-mg (ϳ93 Ci/subject) dose of [ 14 C]ezlopitant. The total recovery of administered radioactive dose was 82.8 ؎ 5.1, with 32.0 ؎ 4.2% in the urine and 50.8 ؎ 1.4% in the feces. Mean observed maximal serum concentrations for ezlopitant and total radioactivity were achieved at ϳ2 h after oral administration; thus, ezlopitant was rapidly absorbed. Ezlopitant was extensively metabolized in humans, since no unchanged drug was detected in urine and feces. The major pathway of ezlopitant in humans was the result of the oxidation of the isopropyl side chain to form the -hydroxy and -1-hydroxy (M16) metabolites. M16 and ,-1-dihydroxy (1,2-dihydroxy, M12) were identified as the major circulating metabolites accounting for 64.6 and 15.4% of total circulating radioactivity, respectively. In feces, the major metabolite M14 was characterized as the propionic acid metabolite and formed by further oxidation of the -hydroxy metabolite. The urinary metabolites were the result of cleaved metabolites caused by oxidative dealkylation of the 2-benzhydryl-1-aza-bicyclo[2.2.2]oct-3-yl moiety. The metabolites (M1A, M1B, and M4), approximately 34% of the total radioactivity in urine, were identified as benzyl amine derivatives. These were polar metabolites that were further characterized using the reaction with dansyl chloride to derivatize the primary amines and phenol moieties to less polar analytes. The other metabolites were the result of O-demethylation, dehydrogenation of the isopropyl group, and oxidation on the quinuclidine moiety.Despite the significant progress made over the past decade in the development of more effective and better tolerated agents to prevent chemotherapy-induced emesis, it still remains a significant, unresolved issue in a number of clinical situations, including cisplatininduced delayed emesis, and multiple and very-high-dose chemotherapy (Roila, 1996;Frakes et al., 1997). Numerous neurotransmitters have been implicated in triggering emesis; however, substance P (SP), an 11-amino acid neuropeptide of the tachykinin family of peptides, by virtue of its localization in both gut and central nervous system, and its ability to produce vomiting when injected in ferrets, is thought to play a key role in emetic response (Watson et al., 1995a). SP binds to a specific neuroreceptor, neurokinin 1 (NK1), and therefore, a number of nonpeptide compounds that selectively block the NK1 receptor have been evaluated as the antiemetic agents (Watson et al., 1995b;Gardner et al., 1996;Gonsalves et al., 1996;Grélot et al., 1998;Diemunsch and Grelot, 2000).Ezlopitant, (2-benzhydryl-1-aza-bicyclo[2.2.2]oct-3-yl)-(5-isopropyl-2-methoxy-benzyl)-amine ( Fig. 1), is a highly potent and selective NK1 receptor antagonist with a K i of 0.4 nM (Evangelista, 200...

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Pharmacokinetics of ezlopitant, a novel non-peptidic neurokinin-1 receptor antagonist in preclinical species and metabolite kinetics of the pharmacologically active metabolites

Cited by 16 publications

References 8 publications

The Neurokinin 1 Receptor Antagonist, Ezlopitant, Reduces Appetitive Responding for Sucrose and Ethanol

The Neurokinin 1 Receptor Antagonist, Ezlopitant, Reduces Appetitive Responding for Sucrose and Ethanol

Central Nervous System Pharmacokinetics of the Mdr1 P-Glycoprotein Substrate CP-615,003: Intersite Differences and Implications for Human Receptor Occupancy Projections from Cerebrospinal Fluid Exposures

Metabolism, Pharmacokinetics, and Excretion of a Nonpeptidic Substance P Receptor Antagonist, Ezlopitant, in Normal Healthy Male Volunteers: Characterization of Polar Metabolites by Chemical Derivatization with Dansyl Chloride

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