Following administration of syrup of ipecac (peripheral emetic stimuli) vomiting was observed in 33% (4 of 12) of Beagle dogs treated with CERENIA Tablets and in 83% (10 of 12) of Beagle dogs treated with placebo tablets. Following administration of apomorphine (central emetic stimuli), vomiting was observed in 33% (4 of 12) of Beagle dogs treated with CERENIA Tablets and 100% (12 of 12) of Beagle dogs treated with placebo tablets. In laboratory model studies, CERENIA Tablets dosed at a minimum of 2 mg/kg BW reduced the number of emetic events associated with established neural (central) and humoral (peripheral) stimuli. Potential of substance P antagonists as antiemetics. In vivo model studies in dogs have shown that maropitant has antiemetic effectiveness against both central and peripheral emetogens including apomorphine, and syrup of ipecac. 1 By inhibiting the binding of substance P within the emetic center, maropitant provides broad-spectrum effectiveness against neural (central) and humoral (peripheral) causes of vomiting. Substance P is found in significant concentrations in the nuclei comprising the emetic center and is considered the key neurotransmitter involved in emesis. Maropitant is a neurokinin 1 (NK 1) receptor antagonist which acts by inhibiting the binding of substance P, a neuropeptide of the tachykinin family. Vomiting is a complex process coordinated centrally by the emetic center which consists of several brainstem nuclei (area postrema, nucleus tractus solitarius, dorsal motor nucleus of the vagus) that receive and integrate sensory stimuli from central and peripheral sources and chemical stimuli from the circulation and the cerebro-spinal fluid. Plasma protein binding of maropitant was high (99.5%). Based upon in vitro enzyme kinetics, involvement of a high capacity enzyme (CYP3A12) may contribute to this return to dose linearity. However as doses increase (20-50 mg/kg PO), dose proportionality is re-established. Based on in vitro enzyme kinetics data, it is believed that the non-linear kinetics may be partially associated with saturation of the low capacity enzyme (CYP2D15). The hepatic metabolism of maropitant involves two cytochrome P-450 isoenzymes: CYP2D15 and CYP3A12. Urinary recovery of maropitant and its major metabolite was minimal (<1% each). An accumulation ratio of 1.5 was observed following once-daily use of maropitant for five consecutive days at 1 mg/kg (SC) or 2 mg/kg (PO). Systemic clearance of maropitant following IV administration was 970, 995, and 533 mL/hr/kg at doses of 1, 2 and 8 mg/kg, respectively. Greater than dose-proportional drug exposure can be expected with an increase in dose (1-16 mg/kg PO). Although hepatic first-pass metabolism contributed to the relatively low bioavailability after an oral dose, prandial status does not significantly affect the extent of oral bioavailability. Oral bioavailability may be underestimated due to the presence of nonlinear kinetics and the resulting longer T ½ seen after intravenous (IV) administration. The absolute bioavailability of maropitant was much higher following SC injection (91% at 1 mg/kg) than after PO administration (24% at 2 mg/kg). Pharmacokinetic Parameters in Beagle Dogs (Mean±SD or range)
0 Comments
Leave a Reply. |
Details
AuthorWrite something about yourself. No need to be fancy, just an overview. ArchivesCategories |