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J Pharmacol Exp Ther. 2018 Feb;364(2):156-169. doi: 10.1124/jpet.117.244079. Epub 2017 Nov 27.

Nonclinical Cardiovascular Studies of Prucalopride, a Highly Selective 5-Hydroxytryptamine 4 Receptor Agonist.

Author information

1
Nonclinical Development, Shire, Basingstoke, United Kingdom (K.C., C.B.); Shire-Movetis, Turnhout, Belgium (J.H.D.M., J.A.J.S.); Biopta Ltd, Glasgow, United Kingdom (L.C.); Java Clinical Research, Dublin, Ireland (J.M.); and Nonclinical Development, Shire, Lexington, Massachusetts (K.D., P.R.W.).
2
Nonclinical Development, Shire, Basingstoke, United Kingdom (K.C., C.B.); Shire-Movetis, Turnhout, Belgium (J.H.D.M., J.A.J.S.); Biopta Ltd, Glasgow, United Kingdom (L.C.); Java Clinical Research, Dublin, Ireland (J.M.); and Nonclinical Development, Shire, Lexington, Massachusetts (K.D., P.R.W.) paulrwade@comcast.net.

Abstract

Patients with chronic constipation benefit from treatment with 5-hydroxytryptamine 4 (5-HT4) receptor agonists. However, the first-generation 5-HT4 receptor agonists cisapride and tegaserod were withdrawn from the market owing to rare cardiovascular adverse events that were not 5-HT4-receptor-related but due to the lack of selectivity of these drugs. Here we report the nonclinical cardiovascular profile of the selective 5-HT4 receptor agonist prucalopride. To assess its non-5-HT4 receptor-mediated effects on cardiovascular electrophysiological parameters, in vitro studies were performed in human ether-à-go-go-related gene-transfected cells, guinea pig ventricular myocytes and papillary muscle preparations, rabbit and dog Purkinje fibers, and the Langendorff rabbit heart. In vivo experiments were performed in a rabbit model for drug-induced proarrhythmogenesis, in anesthetized guinea pigs, and anesthetized and conscious dogs. In addition, human platelet aggregation and coronary artery contraction were studied to exclude interactions that have been suggested to mediate the cardiovascular effects of tegaserod. Effects at 5-HT4 receptors were evaluated in piglet and human atrial myocardium, and in anesthetized pigs. Finally, cardiovascular endpoints were investigated in chronic, repeated-dose toxicology studies at very high prucalopride doses in rats and dogs. No relevant effects were observed in any of the cardiovascular studies at concentrations at least 50 times the therapeutic plasma level. Only in pigs were minor and transient increases in heart rate and blood pressure noted upon first exposure to prucalopride, at plasma levels at least 10 times higher than human therapeutic plasma levels. Prucalopride may thus provide therapeutic benefit without the cardiovascular risks reported for other 5-HT4 receptor agonists.

PMID:
29180358
DOI:
10.1124/jpet.117.244079

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