THE TACHYKININ NK1 RECEPTOR ANTAGONIST PD-154075 BLOCKS CISPLATIN-INDUCED DELAYED EMESIS IN THE FERRET

The activity of a selective tachykinin NK1 receptor antagonist, PD 154 075 zofuran)-CH2OCO]-(R)-alpha-MeTrp-(S)-NHCH(CH3)Ph), was examined in radioligand binding studies, in a [Sar(9),Met(O-2)(11)]substance P-in duced foot-tapping model in the gerbil, and in cisplatin-induced acute and delayed emesis in the ferret. In radioligand binding studies, PD 154075 showed nanomolar affinity for the human, guinea-pig, gerbil, do g and ferret NK1 receptors with an approximate 300 times lower affinit y for the rodent NK1 receptor. Using NK2, NK3 receptors and a range of other receptor ligands, PD 154075 was shown to exhibit a high degree of selectivity and specificity for the human type NK1 receptor. Follow ing subcutaneous administration PD 154075 dose dependently (1-100 mg/k g) antagonised the centrally mediated [Sar(9),Met(O-2)(11)] substance P-induced foot tapping in the gerbil with a minimum effective dose (ME D) of 10 mg/kg. The ability of PD 154075 to readily penetrate into the brain following oral administration was confirmed by its extraction a nd high performance liquid chromatography assay from the rat brain. PD 154075 was shown to achieve a relatively fast and sustained brain con centration (brain/plasma ratios ranged from 0.27 to 0.41 during the ti me period of 0.25-12 h). Further pharmacokinetic studies revealed that the absolute oral bioavailability of PD 154075 in the rat was (mean /- S.D.) 49 +/- 15%. PD 154075 (1-30 mg/kg, i.p.) dose dependently ant agonised the acute vomiting and retching in the ferret measured for 4 h following administration of cisplatin (10 mg/kg, i.p.) with a MED of 3 mg/kg. The administration of a lower dose of cisplatin (5 mg/kg, i. p,) in the ferret induces both an acute (day 1) and delayed (days 2 an d 3) phase of emesis. The i.p. administration of PD 154075, 10 mg/kg t hree times a day for 3 days, almost completely blocked both the acute and delayed emetic responses. In the same study, the 5-HT3 receptor an tagonist ondansetron (1 mg/kg, i.p., t.i.d.) was also very effective a gainst the acute emetic response observed during the first 4 h followi ng cisplatin, but it was only weakly active against the delayed respon se. In conclusion, PD 154075 is a selective and specific high affinity NK, receptor antagonist with good oral bioavailability which is effec tive against both acute and delayed emesis induced by cisplatin in the ferret.