Brain Penetration of Aprepitant, a Substance P Receptor Antagonist, in Ferrets

Huskey, Su-Er W.; Dean, Brian; Bakhtiar, Ray; Sánchez, Rosa I.; Tattersall, F.D.; Rycroft, W.; Hargreaves, Richard; Watt, Alan P.; Chicchi, Gary G.; Keohane, Carol-Ann; Hora, Donald F.; Chiu, Shuet‐Hing Lee

doi:10.1124/dmd.31.6.785

Cited by 47 publications

(27 citation statements)

References 25 publications

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“…In ferrets, administration of aprepitant results in formation of metabolites with affinity for NK 1 R (Huskey et al, 2003). However, the level of metabolites detected in ferret brain were much (Ͼ4-fold) lower than the parent compound aprepitant.…”

Section: Discussionmentioning

confidence: 90%

Neurokinin 1 Receptor Antagonists: Correlation between in Vitro Receptor Interaction and in Vivo Efficacy

Lindström¹,

Mentzer²,

Påhlman³

et al. 2007

J Pharmacol Exp Ther

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We compared the neurokinin 1 receptor (NK 1 R) antagonists aprepitant, CP-99994 [(2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine], and ZD6021 [3-cyano-N-((2S)-2-(3,4-dichlorophenyl)-4-[4-[2-(methyl-(S)-sulfinyl)phenyl]piperidino]butyl)-N-methyl]napthamide]] with respect to receptor interactions and duration of efficacy in vivo. In Ca 2ϩ mobilization assays (fluorometric imaging plate reader), antagonists were applied to human U373MG cells simultaneously with or 2.5 min before substance P (SP). In reversibility studies, antagonists were present for 30 min before washing, and responses to SP were repeatedly measured afterward. The compounds were administered i.p. to gerbils, and the gerbil foot tap (GFT) response was monitored at various time points. The NK 1 R receptor occupancy for aprepitant was determined in striatal regions. Levels of compound in brain and plasma were measured. Antagonists were equipotent at human NK 1 R and acted competitively with SP. After preincubation, aprepitant and ZD6021 attenuated the maximal responses, whereas CP-99994 only shifted the SP concentration-response curve to the right. The inhibitory effect of CP-99994 was over within 30 min, whereas for ZD6021, 50% inhibition still persisted after 60 min. Aprepitant produced maximal inhibition lasting at least 60 min. CP-99994 (3 mol/kg) inhibited GFT by 100% 15 min after administration, but the effect declined rapidly together with brain levels thereafter. The efficacy of ZD6021 (10 mol/kg) lasted 4 h and correlated well with brain levels. Aprepitant (3 mol/kg) inhibited GFT and occupied striatal NK 1 R by 100% for Ͼ48 h despite that brain levels of compound were below the limit of detection after 24 h. Slow functional reversibility is associated with long-lasting in vivo efficacy of NK 1 R antagonists, whereas the efficacy of compounds with rapid reversibility is reflected by their pharmacokinetics.The neurokinins substance P (SP), neurokinin (NK) A (NKA), and NKB belong to the tachykinin peptide family (Severini et al., 2002). The tachykinin receptors are divided into three subtypes: NK 1 R, NK 2 R, and NK 3 R. The rank order of potency of the endogenous tachykinins are: for NK 1 R, SP Ն NKA Ͼ NKB; for NK 2 R, NKA Ͼ NKB Ͼ SP; and for NK 3 R, NKB Ͼ NKA Ͼ SP (for review, see Pennefather et al., 2004). Hemokinin-1 and endokinins A and B are relatively new mammalian members of the tachykinin family but appear to have similar receptor pharmacology as SP (Page, 2006). On the other hand, endokinins C and D have negligible affinity for known NK receptors (Page, 2006).Preclinical research has implicated especially the NK 1 R as being involved in several pathological disorders, including emesis, asthma, psychiatric disorders, gastrointestinal disorders, pain, migraine, inflammation, and urinary bladder disorders. This has led to the subsequent development of selective and potent NK 1 R antagonists (for recent review, see Quartara and Altamura, 2006). However, so far, only aprepitant has reached the market for treatment of chemothe...

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Section: Discussionmentioning

confidence: 90%

Neurokinin 1 Receptor Antagonists: Correlation between in Vitro Receptor Interaction and in Vivo Efficacy

Lindström¹,

Mentzer²,

Påhlman³

et al. 2007

J Pharmacol Exp Ther

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“…There is strong evidence in the literature to suggest that the beneficial effects of NK-1 receptor antagonists on chemotherapy-induced nausea and vomiting are dependent on brain penetration and subsequent binding to receptors in the brain (King, 1990;Huskey et al, 2003). Therefore, the pharmacokinetics and brain concentrations of a novel NK-1 receptor antagonist, casopitant, were examined in ferrets, a species previously used to assess the therapeutic potential of this drug as a treatment for nausea and vomiting following chemotherapy.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics and Brain Penetration of Casopitant, a Potent and Selective Neurokinin-1 Receptor Antagonist, in the Ferret

Minthorn¹,

Mencken²,

King³

et al. 2008

Drug Metab Dispos

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ABSTRACT:The pharmacokinetics and brain penetration of the novel neurokinin (NK) The tachykinins are a family of peptide neurotransmitters that mediate the release of intracellular calcium by binding to a group of transmembrane receptors called neurokinins (NK). NK-1 receptor antagonists are believed to confer antiemetic activity by suppressing the activity of the nucleus tractus solitarius, which is the point at which the vagal afferents from the gastrointestinal tract converge with inputs from the area postrema and other regions of the brain believed to be important in the control and initiation of emesis. Casopitant (GW679769) is a potent and selective NK-1 receptor antagonist. It is currently in Phase III clinical development for the treatment of chemotherapy-induced nausea and vomiting, as well as postoperative nausea and vomiting. Previous animal and human studies have shown that casopitant has antiemetic activity in vivo (Arpornwirat et al., 2006;King, 2006;Rolski et al., 2006).-The ferret is known to respond to the full spectrum of agents recognized to induce emesis in humans (King, 1990). The cisplatininduced acute and delayed emesis models in the ferret have been used extensively to identify the antiemetic potential of novel drug therapies, including casopitant. In these models, casopitant has shown a prolonged effect in the attenuation of cisplatin-induced emesis. This suggests that casopitant may be helpful in treating human patients undergoing chemotherapy who experience persistent nausea and vomiting for several days after drug treatment. Brain penetration and subsequent receptor occupancy are expected to be important factors that influence the onset and duration of the pharmacologic effects of casopitant. It is not known whether the major metabolites of casopitant have NK-1 antagonist activity or if the prolonged pharmacodynamic effects of casopitant observed in the ferret are caused by casopitant itself, one of its metabolites, or a combination. A better understanding of the pharmacokinetics and drug metabolism in the ferret is essential to elucidating the pharmacodynamic contribution of casopitant and its circulating metabolite(s) to the therapeutic effects observed in ferret emesis models.Selective NK-1 receptor antagonists provide incremental improve- Article, publication date, and citation information can be found at

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“…Of note, however, the clinically available NK 1 receptor antagonist aprepitant is administered for the prevention of CINV but not for the treatment of nausea and vomiting, which is possibly due to its relatively slow distribution to the brain. 32,33) Here, we showed the immediate antiemetic activity of the oral administration of FK886 against cisplatin-induced delayed emesis. This is consistent with previous reports of the rapid and efficient distribution of FK886 into the brain in several species other than ferrets.…”

Section: )mentioning

confidence: 99%

Antiemetic Effect of a Potent and Selective Neurokinin-1 Receptor Antagonist, FK886, on Cisplatin-Induced Acute and Delayed Emesis in Ferrets

Furukawa

Nakayama

Imazumi

et al. 2014

Biological & Pharmaceutical Bulletin

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The antiemetic effect of a potent and selective neurokinin-1 (NK 1 ) receptor antagonist, FK886 ([3,5-bis(trifluoromethyl) phenyl][(2R)-2-(3-hydroxy-4-methylbenzyl)-4-{2-[(2S)-2-(methoxymethyl)morpholin-4-yl]ethyl}piperazin-1-yl] methanone dihydrochloride), on cisplatin-induced acute and delayed emesis in ferrets was studied. Intravenous administration of FK886 dose-dependently inhibited cisplatin (10 mg/kg)-induced acute emesis with a minimum effective dose (MED) of 0.32 mg/kg. In the same study, oral FK886 administered 8 h prior to cisplatin also dose-dependently inhibited the acute emesis during the 4-h observation period with an MED of 3.2 mg/kg. Further, when given by repeated oral administration of ≥1.6 mg/kg at 12-h intervals, the first dose being administered 1 min before cisplatin, FK886 significantly decreased the number of emetic responses in cisplatin (5 mg/kg)-induced delayed emesis. In the same study, oral FK886 (3.2 mg/kg) repeatedly administrated at 12-h intervals, the first dose being administered 36 h post cisplatin, also significantly attenuated the delayed emesis. Pharmacokinetic data in ferrets showed that plasma FK886 reached a maximum concentration within 0.5 h of administration, suggesting rapid oral absorption. In addition, rapid brain penetration of FK886 was suggested by complete and near complete inhibition of GR73632-and copper sulfate-induced emesis, respectively, by low-dose intravenous FK886 administered shortly before the emetogens. These results suggest that FK886 is an orally available NK 1 receptor antagonist which is effective against both the acute and delayed emesis induced by cisplatin. Because of its therapeutic efficacy on the delayed emesis and rapid brain distribution after oral administration, FK886 may have potential as an antiemetic agent that can be used for interventional treatment of chemotherapy-induced delayed emesis.Key words FK886; neurokinin-1 antagonist; ferret emesis; cisplatin; GR73632; copper sulfate Nausea and vomiting are distressing symptoms that significantly detract from a patient's overall quality of life and their recovery during medical treatment. Nausea and vomiting both occur as symptoms of many diseases and as side effects of medical treatments, including cancer chemotherapy, radiotherapy, and general anesthesia in surgery. 1) Chemotherapy-induced nausea and vomiting (CINV) is perceived to be a major adverse effect of treatment by patients. 2) CINV may occur within hours of chemotherapy (acute phase) or be delayed until after the first 24 h, and then persist for several days (delayed phase). During the acute phase, chemotherapeutic agents induce serotonin (5-HT) release from enterochromaffin cells which stimulates local 5-HT 3 receptors on gastrointestinal vagal afferent nerves to initiate the vomiting reflex. [3][4][5] This may explain why 5-HT 3 antagonists have been shown to sufficiently control chemotherapy-induced acute emesis. [6][7][8] In contrast, 5-HT 3 antagonists are poorly effective against delayed emesis, 9,10) and the underlying ...

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Brain Penetration of Aprepitant, a Substance P Receptor Antagonist, in Ferrets

Cited by 47 publications

References 25 publications

Neurokinin 1 Receptor Antagonists: Correlation between in Vitro Receptor Interaction and in Vivo Efficacy

Neurokinin 1 Receptor Antagonists: Correlation between in Vitro Receptor Interaction and in Vivo Efficacy

Pharmacokinetics and Brain Penetration of Casopitant, a Potent and Selective Neurokinin-1 Receptor Antagonist, in the Ferret

Antiemetic Effect of a Potent and Selective Neurokinin-1 Receptor Antagonist, FK886, on Cisplatin-Induced Acute and Delayed Emesis in Ferrets

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