A Phase 1 interventional study of Acetaminophen and Talinolol in Gastrointestinal Motility Disorder, sponsored by University Medicine Greifswald. Completed at 1 site in Germany. Open to participants aged 18 Years to 45 Years, including healthy volunteers. Per ClinicalTrials.gov, last updated 2012-07-09.
Sponsored by University Medicine Greifswald · Phase 1, Interventional, and Basic science
To visualize the localization and to measure the volume of water in the small intestine by T2-weighted MRI imaging after oral administration of 240 ml water (non-caloric water) and after administration of 240 ml water containing 25.5 g sucrose (105 kcal, caloric water).
To measure pharmacokinetics of the probe-drugs paracetamol, talinolol and amoxicillin after oral administration dissolved in 240 ml non-caloric and in 240 ml caloric water.
After swallowing, a drug first is deposited in the stomach together with the co-swallowed water. However, the stomach is not the major place of drug absorption. Therefore, the kinetics of gastric emptying plays a crucial role for the absorption process. In case of dissolved or finely suspended drug particles, gastric emptying of the drugs occurs together with gastric contents. The emptied liquid enters the small intestine where it is absorbed. Under fasting conditions, the emptied phase consists of the water that was co-swallowed with the drug (in clinical studies typically 240 ml) together with a small volume of gastric juice. Under fed conditions, the emptied liquid phase is a caloric suspension. It is known that both the gastric emptying and the intestinal absorption of pure water are rapid leading usually to rapid absorption of water soluble drugs that are taken under fasting conditions. In the contrary, delayed absorption under postprandial conditions is typically related to delayed gastric emptying. However, velocity and extent of intestinal filling and the absorption rate of the liquid phase from gut lumen are unknown.
Therefore, it is the primary objective of the study to determine the gastric emptying kinetics of 240 ml water (non-caloric water) and of 240 ml water containing 25.5 g sucrose (105 kcal, caloric water), the respective intestinal filling and the absorption rate of the intestinal liquid using water sensitive magnetic resonance imaging (MRI).
To evaluate the functional meaning of gastric emptying, intestinal filling and water uptake for oral drug absorption which are swallowed with non-caloric and caloric water, pharmacokinetics of paracetamol, talinolol and amoxicillin will be studied after administration with 240 ml non-caloric and 240 ml caloric water, respectively.
Paracetamol (acetaminophen) was chosen, because it is rapidly and completely absorbed from all parts of the gut. The time of its appearance in blood is expected to be a surrogate for the rate of gastric emptying. It is hypothesized that caloric content of the water for administration does not influence the extent of paracetamol absorption.
Talinolol represents a well established probe drug for the intestinal efflux transport protein ABCB1. Because expression of ABCB1 increases along the small intestine (duodenum\<jejunum\<ileum), we hypothesize, that administration of talinolol with caloric water leads to lower bioavailability and increase of the fecal excretion of the drug.
Amoxicillin acts as a probe drug for intestinal drug uptake via the dipeptide transporter PEPT1 which is predominately expressed in proximal parts of the small intestine ((duodenum>jejunum>ileum). Because of this region-specific expression, we hypothesize, that administration of amoxicillin with caloric water is associated with lower bioavailability.
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Exclusion Criteria:
500 mg paracetamol, 50 mg talinolol and 500 mg amoxicillin dissolved in 240 ml non-caloric water immediately before administration after overnight fasting
Drug: Acetaminophen · Drug: Talinolol · Drug: Amoxicillin · Other: non-caloric water
500 mg paracetamol, 50 mg talinolol and 500 mg amoxicillin dissolved in 240 ml caloric water immediately before oral administration after overnight fasting
Drug: Acetaminophen · Drug: Talinolol · Drug: Amoxicillin · Other: caloric water
administration of 500 mg paracetamol
administration of 50 mg talinolol
administration of 500 mg amoxicillin
administration of 240 ml water
administration of 240 ml caloric water (containing 25.5 g sucrose)
Correlation between volume of water in stomach and AUC of study medication
Time frame: 0 to 48 h
area under the concentrations-time curve (AUC)
Time frame: 0, 5, 10, 15, 20, 30, 40, 50, 60, 75, 90, 105 min and 2, 3, 4, 6, 8, 12, 24 and 48 h after drug administration
maximum concentration (Cmax)
Time frame: 0, 5, 10, 15, 20, 30, 40, 50, 60, 75, 90, 105 min and 2, 3, 4, 6, 8, 12, 24 and 48 h after drug administration
volumen of water in stomach
Dynamic enhanced MR examination gradient-echo T2-weighted HASTE images (TR 1900 ms, TR 111 ms, flip-angle 0) will be acquired on a 1.5T MRI. A tube filled with 20 ml water will be fitted on the abdomen of the volunteers in order to have an internal reference for imaging.
Time frame: before and 1.5, 6.5, 11.5, 16.5, 21.5, 26.5, 31.5, 36.5, 41.5, 46.5, 51.5, 56.5, 61.5, 66.5, 71.5, 76.5, 81.5, 86.5, 91.5, 96.5, 101.5, 106.5, 111.5, and 116.5 min after administration of the study medication
volumen of water in small intestine
Dynamic enhanced MR examination gradient-echo T2-weighted HASTE images (TR 1900 ms, TR 111 ms, flip-angle 0) will be acquired on a 1.5T MRI. A tube filled with 20 ml water will be fitted on the abdomen of the volunteers in order to have an internal reference for imaging.
Time frame: before and 1.5, 6.5, 11.5, 16.5, 21.5, 26.5, 31.5, 36.5, 41.5, 46.5, 51.5, 56.5, 61.5, 66.5, 71.5, 76.5, 81.5, 86.5, 91.5, 96.5, 101.5, 106.5, 111.5, and 116.5 min after administration of the study medication
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University Medicine Greifswald