Pharmacokinetics of an Oral Drug (Acetaminophen) Administered at Various Times in Relation to Subcutaneous Injection of Exenatide (Exendin‐4) in Healthy Subjects

Abstract

Exenatide is an incretin mimetic with potential glucoregulatory activity in type 2 diabetes. This randomized, single-blind, placebo-controlled 6-way crossover study assessed exenatide's effect on acetaminophen pharmacokinetics. Of 40 randomized healthy subjects, 39 completed the study. On the placebo day, acetaminophen (1000 mg) was ingested and placebo injected subcutaneously at 0 hours. On exenatide days, acetaminophen was ingested at -1, 0, +1, +2, and +4 hours, relative to the 10 mug exenatide injected subcutaneously at 0 hours. With exenatide injection, mean plasma acetaminophen AUC(0-12 h) values were reduced by 11% to 24% (vs placebo). Peak plasma acetaminophen concentrations were similar for the -1-hour and placebo groups and reduced by 37% to 56% at other times. The most frequent adverse events were generally mild to moderate nausea and vomiting. Exenatide treatment concurrent with or preceding acetaminophen ingestion slowed acetaminophen absorption but had minimal effect on the extent of absorption.

Assessment of pharmacokinetic drug-drug interaction between pradigastat and acetaminophen in healthy subjects

“…SD standard deviation analgesic and antipyretic. Acetaminophen is used as a marker to determine effects on gastric emptying as absorption of acetaminophen is sensitive to both delayed and accelerated gastric emptying [9][10][11].…”

“…Gastric emptying is initiated by the meal and drugs that impact gastric motility are expected to delay gastric emptying induced by meal consumption [9,10]. Hence, administration of acetaminophen at various time intervals relative to the timing of a meal in the presence and absence of pradigastat was designed to evaluate the effect of pradigastat on gastric emptying.…”

“…Following oral administration, acetaminophen is quickly absorbed in the proximal small intestine with a Tmax of 10 to 90 min depending on the formulation and eliminated with a half-life of 2-3 h [8]. The rate of gastric emptying largely determines the absorption and efficacy profile of acetaminophen and hence, is used as a marker for gastric emptying/motility [9,10]. Therefore, this study was conducted to determine if acetaminophen's pharmacokinetic profile is altered when administered relative to meal time in the presence of pradigastat.…”

The Effect of Exenatide and Erythromycin on Postprandial Symptoms and Their Relation to Gastric Functions

“…The T max of exenatide after subcutaneous administration is 1–2 h [17], suggesting that high circulating levels were achieved for the entire 45 min of the fasting and postprandial scanning. In addition, participants received erythromycin 2 mg/kg or saline intravenously over 20 min, starting at the initiation of SPECT acquisition.…”

Exenatide effects on glucose metabolism and metabolic disorders common to overweight and obese patients with type 2 diabetes

“…Another interesting glucoregulatory mechanism exhibited by exenatide treatment is its effect to reduce the rate of glucose entering the circulation following a meal, as inferred from the slowed appearance of concurrently administered oral acetaminophen [Kolterman et al, 2003;Blase et al, 2005]. Exenatide slows gastric emptying of both solids and liquids in a dosedependent manner.…”