Effects of NK1 receptors on gastric motor functions and satiation in healthy humans: results from a controlled trial with the NK1 antagonist aprepitant

Abstract

Aprepitant, an NK1 receptor antagonist, is approved for the treatment of chemotherapy-induced or postoperative emesis by blocking NK1 receptors in the brain stem vomiting center. The effects of NK1 receptors on gastric functions and postprandial symptoms in humans are unclear; a single, crossover study did not show a significant effect of aprepitant on gastrointestinal transit. Our aim was to compare, in a randomized, double-blind, placebo-controlled, parallel-group study (12 healthy volunteers per group), the effects of aprepitant vs. placebo on gastric emptying of solids (by scintigraphy) with a 320-kcal meal, gastric volumes (GVs; fasting and accommodation by single photon emission-computed tomography ), satiation [maximum tolerated volume (MTV)], and symptoms after a dyspeptogenic meal of Ensure. Aprepitant (125 mg on , followed by 80 mg on) or placebo, one tablet daily, was administered for 5 consecutive days. Statistical analysis was by unpaired rank sum test, adjusted for sex difference and body mass index. To assess treatment effects on symptoms, we incorporated MTV in the model. Aprepitant increased fasting, postprandial, and accommodation GV and tended to increase volume to fullness and MTV by ~200 kcal. However, aprepitant increased aggregate symptoms, nausea, and pain scores after ingestion the MTV of Ensure. There was no significant effect of aprepitant on gastric half-emptying time of solids. We conclude that NK1 receptors are involved in the control of GV and in determining postprandial satiation and symptoms. Further studies of the pharmacodynamics and therapeutic role of NK1 receptor antagonists in patients with gastroparesis and dyspepsia are warranted. Aprepitant increases fasting, postprandial, and accommodation gastric volumes. Aprepitant increases volume to fullness and maximum tolerated volume during a nutrient drink test. NK1 receptors are involved in the control of gastric volume and in determining postprandial satiation and symptoms.

Dipeptidyl Peptidase 4 Inhibition Increases Postprandial Norepinephrine via Substance P (NK1 Receptor) During RAAS Inhibition

“…The finding that cotreatment with the NK1/substance P receptor antagonist aprepitant abolished the increase in norepinephrine suggests that substance P mediates stimulation of the sympathetic nervous system. Importantly, aprepitant does not significantly affect gastric transit time [35]. The finding that norepinephrine was increased by sitagliptin during valsartan as well as during ramipril, however, indicates that the mechanism involves a pharmacodynamic interaction between substance P and the RAAS rather than a pharmacokinetic effect of ACE inhibition and DPP4 inhibition on substance P. Unfortunately, we were not able to measure endogenous substance P using a specific assay in this study.…”

Gastroparesis: a turning point in understanding and treatment

“…Also, neurokinin antagonists are approved for the treatment of chemotherapy-induced emesis 126. Among these drugs, aprepitant, increases gastric accommodation127 and improves some digestive symptoms in patients with gastroparesis,128 but does not affect GE 127. Although the APRON Trial failed to show positive results on the primary end point of nausea, several other secondary end points showed improvement with aprepitant 128.…”

Pharmacokinetics of maropitant citrate after oral administration of multiple doses in adult horses

“…However, a study in mice showed that maropitant administration reduced intestinal motility and delayed intestinal transit time of labeled luminal contents (Mikawa et al, ). Similarly, humans using similar NK‐1 receptor antagonists have reported side effects of constipation in up to 16% of patients studied in one population (Jacob et al, ; Li et al, ). Peer‐reviewed data are unavailable describing intestinal motility disorders associated with maropitant in species other than mice, and further investigation is warranted prior to administering maropitant to horses at risk for gastrointestinal impaction.…”