Helmut Thomas

Effect of the ghrelin receptor agonist TZP-101 on colonic transit in a rat model of postoperative ileus.

Ghrelin, the natural ligand of the growth hormone secretagogue receptor (ghrelin receptor), is an orexigenic gut hormone with prokinetic action in the upper gastrointestinal tract. Previously we have shown in a rodent model of postoperative ileus that the synthetic ghrelin receptor agonist TZP-101 prevents the delay in gastric emptying and improves small intestinal transit. The goal of the present study was to investigate whether TZP-101 affects colonic transit and food intake in rats with postoperative ileus. Fasted rats were treated with morphine and subjected to laparotomy under isoflurane anesthesia. Following surgery the animals were placed in clean home cages and fecal pellet output and food intake were monitored for 48 h. TZP-101 or vehicle were administered as 3 i.v. bolus infusions at 0 h, 2 h and 4 h post-surgery. TZP-101 (0.03-1 mg/kg) dose-dependently decreased the time to first bowel movement and increased fecal pellet output measured at 12 h and 24 h post-surgery compared to the vehicle. The administration of TZP-101 was not associated with a significant alteration in food intake. In conclusion, this study provides the first experimental evidence that a novel ghrelin receptor agonist improves large bowel function in rats with postoperative ileus, suggesting that TZP-101 may be useful in the clinic to accelerate upper gastrointestinal transit and to shorten the time to the first bowel movement following surgery.

Contribution of Protein Binding to the Pharmacokinetics of the Ghrelin Receptor Agonist TZP-101 in Healthy Volunteers and Adults with Symptomatic Gastroparesis Two Randomized, Double-Blind Studies and a Binding Profile Study

AbstractBackground and objective: TZP-101 is a selective, small molecule ghrelin receptor agonist in clinical development for the treatment of gastric motility disorders. The objectives of this study was to assess pharmacokinetic parameters of TZP-101 after multiple- and single-dose administration to healthy subjects and patients with gastroparesis, respectively, and to determine the contribution of protein binding to its pharmacokinetic behaviour.n Methods: Pharmacokinetics following 30-minute intravenous infusions of single (160–600 µg/kg) doses of TZP-101 in patients with gastroparesis and multiple (80–600 µg/kg/day) doses of TZP-101 in healthy subjects were characterized. TZP-101 protein binding was measured in human, dog, rat, rabbit and monkey plasma using equilibrium dialysis.n Results: TZP-101 pharmacokinetic profiles were less than dose proportional in both healthy subjects and patients, most likely because of concentrationdependent protein binding. A small volume of distribution (99–180 µL/kg following single doses) and long half-life (10–20 hours) were concentration independent in both healthy subjects and patients. Systemic clearance increased with increasing dose. Incidence of adverse events was not related to dose or treatment (active vs placebo). TZP-101 binding to human plasma proteins (primarily α1-acid glycoprotein) was ≥99% between 5 and 15 µmol/L (2.7 and 8.1 µg/mL) and was significantly higher than in other species.n Conclusions: The pharmacokinetic parameters of TZP-101 in patients with gastroparesis and healthy subjects are comparable and display a similar trend toward increased clearance at higher dose levels resulting in little accumulation of TZP-101 at high dose levels and after multiple dosing. Significant protein binding indicates that the fraction of free drug rather than the total plasma concentration should be taken into consideration for human risk assessment based on animal safety data. Furthermore, the concentration of unbound drug should be considered when optimizing the clinical dose.

Effect of TZP-201, a novel motilin receptor antagonist, in the colon of the musk shrew (Suncus murinus)

Objectives Motilin is the main gut peptide that stimulates propulsive motility in the upper gastrointestinal (GI) tract. Motilin receptors exist in the colon but little is known about their functional role, and species‐dependent differences present a major obstacle to understanding the physiological significance and potential therapeutic implications of motilin receptors in the colon. Our study aimed to define whether a motilin receptor is functionally expressed in the colon of the Asian musk (or house) shrew (Suncus murinus) and to investigate the effect of a novel motilin receptor antagonist, TZP‐201.