Long-lasting anti-emetic effect of T-2328, a novel NK(1) antagonist.

The effect of T-2328 {2-fluoro-4'-methoxy-3'-[[[(2S,3S)-2-phenyl-3-piperidinyl]amino]methyl]-[1,1'-biphenyl]-4-carbonitrile dihydrochloride}, a novel tachykinin NK(1)-receptor antagonist, was examined on cisplatin-induced emesis in ferrets. Cisplatin induced acute emesis in 24 h and delayed emesis during 24 and 72 h, respectively. Ondansetron, a 5-HT(3) antagonist, almost completely blocked the acute emesis and transiently reduced the delayed emesis. In contrast, T-2328 elicited long-lasting anti-emetic effects on both acute and delayed phases by a single intravenous administration. Suppression of delayed emesis was not due to elimination of the acute phase because the delayed emesis was also suppressed by administration after the onset of delayed emesis. Persistent blockade of NK(1) receptors in the brain was demonstrated by inhibition of the NK(1) agonist-induced foot tapping response for over 24 h. An appreciable amount of T-2328 was present in the brain 32 and 72 h after the injection. The NK(1) agonist-induced contractions of isolated ileum in guinea pigs was antagonized with IC(50) values of 1.4 nM in an insurmountable manner. It is likely that T-2328 exerts the long-lasting anti-emetic effect by not only long-term presence in the brain but also its insurmountable inhibition of NK(1) receptors.

Determination of morphine, morphine-3-glucuronide and morphine-6-glucuronide in monkey and dog plasma by high-performance liquid chromatography-electrospray ionization tandem mass spectrometry.

A specific and simultaneous assay of morphine, morphine-3-glucuronide (M-3-G) and morphine-6-glucuronide (M-6-G) in monkey and dog plasma has been developed. These methods are based on rapid isolation using solid phase extraction cartridge, and high-performance liquid chromatography (HPLC)-electrospray ionization (ESI)-tandem mass spectrometric (MSMS) detection. Analytes were separated on a semi-micro ODS column in acetonitrile-formic (or acetic) acid mixed solution. The selected reaction monitoring for assay in monkey and dog plasma, as precursor-->product ion combinations of m/z 286-->286 for morphine, m/z 462-->286 for glucuronides and m/z 312-->312 for internal standard (IS, nalorphine) were used. The linearity of morphine, M-3-G and M-6-G was confirmed in the concentration range of 0.5-50, 25-2500, 2.5-250 ng/ml in monkey plasma, 0.5-100, 25-5000, 2.5-500 ng/ml in dog plasma, respectively. The precision of this assay method, expressed as CV, was less than 15% over the entire concentration range with adequate assay accuracy. Therefore, the HPLC-ESI-MSMS method is useful for the determination of morphine, M-3-G and M-6-G with sufficient sensitivity and specificity in pharmacokinetic studies.