Cevimeline Hydrochloride

Bile acids regulate gastrointestinal motility by mechanisms that are poorly understood. Standard isolated tissue bath assays might not recapitulate in vivo physiology if contractile responses to certain bile acids require direct application to the intestinal mucosa. We sought to determine the feasibility of quantifying longitudinal smooth muscle contractile responses to bile acids from intact segments of everted mouse ileum. Ileum from adult female C57BL/6J mice was isolated, gently everted over a notched metal rod, and mounted in tissue baths. Individual bile acids and agonists of bile acid receptors were added to the baths, and longitudinal smooth muscle contractile responses were quantified by isometric force transduction. Ursodeoxycholic acid robustly increased contractile responses in a dose‐dependent manner. Deoxycholic acid stimulated contractility at low doses but inhibited contractility at high doses. Chenodeoxycholic acid, glycocholic acid, and lithocholic acid did not alter contractility. The dose‐dependent increase in contractility resulting from the application of ursodeoxycholic acid was recapitulated by INT‐777, an agonist of the Takeda G protein‐coupled receptor 5 (TGR5), and by cevimeline, a muscarinic acetylcholine receptor agonist. Agonists to the nuclear receptors farnesoid X receptor, glucocorticoid receptor, pregnane X receptor, vitamin D receptor, and to the plasma membrane epidermal growth factor receptor did not modify baseline contractile patterns. These results demonstrate that gentle eversion of intact mouse ileum facilitates the quantification of longitudinal smooth muscle contractile responses to individual bile acids. Prokinetic effects of ursodeoxycholic acid and low‐dose deoxycholic acid are replicated by agonists to TGR5 and muscarinic acetylcholine receptors.

The organic cation transporter 1 (OCT1) mediates the cell uptake and cytochrome P450 2D6 (CYP2D6) the metabolism of many cationic substrates. Activities of OCT1 and CYP2D6 are affected by enormous genetic variation and frequent drug-drug interactions. Single or combined deficiency of OCT1 and CYP2D6 might result in dramatic differences in systemic exposure, adverse drug reactions, and efficacy. Thus, one should know what drugs are affected to what extent by OCT1, CYP2D6 or both. Here, we compiled all data on CYP2D6 and OCT1 drug substrates. Among 246 CYP2D6 substrates and 132 OCT1 substrates, we identified 31 shared substrates. In OCT1 and CYP2D6 single and double-transfected cells, we studied which, OCT1 or CYP2D6, is more critical for a given drug and whether there are additive, antagonistic or synergistic effects. In general, OCT1 substrates were more hydrophilic than CYP2D6 substrates and smaller in size. Inhibition studies showed unexpectedly pronounced inhibition of substrate depletion by shared OCT1/CYP2D6 inhibitors. In conclusion, there is a distinct overlap in the OCT1/CYP2D6 substrate and inhibitor spectra, so in vivo pharmacokinetics and -dynamics of shared substrates may be significantly affected by frequent OCT1- and CYP2D6-polymorphisms and by comedication with shared inhibitors.