Predicting the emetic liability of novel chemical entities: a comparative study

Abstract

Background and purpose: Emesis is a multi-system reflex, which is usually investigated using in vivo models. The aim of the study is to compare the response induced by emetic compounds across species and investigate whether dogs, ferrets and rats are all similarly predictive of humans.

Experimental approach: A systematic review was carried out and relevant publications were identified from PubMed. The search was restricted to four species (human, dog, ferret, rat) and ten compounds representative of various mechanisms of emesis induction (apomorphine, cisplatin, cholecystokinin octapeptide, copper sulphate, cyclophosphamide, ipecacuanha, lithium chloride, morphine, nicotine, rolipram).

Key results: 1046 publications were reviewed, and 311 were included, the main reason for exclusion was the lack of quantitative data. Emetic or pica data were extracted as incidence, intensity or latency. All three animal species identified emetic liability but interspecies differences for dose sensitivity were detected.

Conclusions and implication: These results suggest that emetic liability can be reliably identified in a common laboratory species such as the rat. However, to evaluate the characteristics of the emetic response, no animal species is a universal predictor of emetic liability and the choice of species should be an informed decision based on the type of compound investigated. Limitations relating to the conduct and reporting of emesis studies were identified, the main ones being the lack of comparable outcome measures between human and animal data, and the limited availability of human data in the public domain.

Figure 1

Flow chart of identified studies. Reproduced and adapted from the PRISMA statement diagram (Moher et al., 2009).

Figure 2

Incidence of emesis, pica and nausea for each drug in human, dog, ferret and rat. Incidence (percentage of individuals developing an emetic response) at each dose is plotted as weighted mean. The data were fitted using a sigmoidal curve (variable slope, normalized). Only the ascending part of the curve was considered for drugs following an inverted U distribution (apomorphine s.c. in the ferret, morphine s.c. in the ferret and morphine i.v. in the dog; inflexion points were determined with a second order polynomial curve; not shown). Note that for clarity, only peripheral modes of administration are shown on the graphs.

Figure 3

Emetic scale for each drug in human, dog, ferret and rat. The emetic scale at each dose is plotted as weighted mean. For each species, an emetic unit is defined as the maximal emetic response to cisplatin. The data were fitted using a second-order polynomial curve.

Figure 4

Latency to the onset of the emetic response for each drug, in human, dog and ferret. The latency at each dose is plotted as weighted mean. The data were fitted using a second-order polynomial curve.

Figure 5

Site(s) of action implicated in the emetic or pica response induced by the ten compounds reviewed. Systemic or i.c.v. apomorphine, morphine and nicotine activate dopamine D₂ and D₃, µ (possibly µ₁) opioid and nicotinic receptors, respectively, in the area postrema (AP) (Laffan and Borison, 1957; Osinski et al., 2005; Rudd and Naylor, 1995; Wang and Borison, 1952), although the possibility of an action on the subjacent nucleus tractus solitarius (NTS) cannot be excluded by such studies. The cytotoxic drugs cisplatin and cyclophosphamide induce the local release of 5-HT from enteroendocrine cells, which activate 5-HT₃ receptors on the peripheral terminals of abdominal vagal afferents (Rudd and Andrews, 2005). Additionally, cisplatin-induced emesis (delayed phase) can be mediated by the area postrema, but the molecular mechanism is not known (Percie du Sert et al., 2009). Abdominal vagal afferents have been implicated in the mechanism by which intragastric ipecacuanha (Andrews and Davis, 1995), copper sulphate (Wang and Borison, 1951) and CCK-8 induce emesis (Lang et al., 1988), although in the case of the latter, a direct action on receptors located on the nodose ganglion (NG) or in the brain stem cannot be excluded. The site of emetic action of lithium chloride has not been investigated but the AP is required for it to induce conditioned taste aversion in the rat (Borison, 1989). A central site of action for the PDE4 inhibitor rolipram is supported by electrophysiological (Carpenter et al., 1988) and isoform distribution studies (Mori et al., 2010), but in contrast to other compounds, the effect of area postrema ablation and vagotomy have not been investigated.