Impact of Two Genetic Variants of OATP1B3 or MRP2 or Rifampin on Systemic Disposition and Biological Efficacy of CCK-8

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to evaluate the impact of genetic variants of OATP 1B3 or MRP 2 on the systemic disposition of endogenously formed CCK-8 and to determine the influence of a single-dose of the transporter inhibitor rifampin (600 mg) on the systemic disposition of endogenously formed CCK-8. Endogenous CCK-8 secretion will be induced by a single-dose standardized liquid mixed meal.

Official Title
-----------------
Impact of Two Genetic Variants of OATP 1B3 or MRP 2 or Rifampin Mediated Transporter Inhibition on Systemic Disposition and Biological Efficacy of CCK-8 in 36 Healthy Male Individuals

Conditions
-----------------
Gastrointestinal Hormones

Intervention / Treatment
-----------------
* Dietary Supplement: mixed meal
* Drug: Rifampin


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: age: 18-45 years sex: male 12 subjects being homozygote wild-type carriers of OATP 1B3 (c.SLCO 1B3 699 AA and c.SLCO 1B3 334 GG) and MRP 2 12 subjects being homozygotes of the MRP 2 variants (genetic loss of function) and homozygote wild-type carriers of OATP 1B3 12 subjects being homozygotes of the OATP 1B3 variants (c.SLCO 1B3 699 GG and c.SLCO 1B3 334 TT) and homozygotes wild-type carriers of MRP 2 BMI: ≥ 19 kg/m2 and ≤ 27 kg/m2 good health as evidenced by the results of the clinical examination, ECG, and the laboratory check-up, which will be judged by the clinical investigator not to differ in a clinical relevant way from the healthy state written informed consent given by the volunteer after being provided with detailed information (both, verbally and written) about the nature, risks, and scope of the clinical trial as well as the expected desirable and adverse effects of the drug Exclusion Criteria: hepatic and renal diseases and/or pathological findings, which might interfere with pharmacokinetics and pharmacodynamics of the study medication gastrointestinal diseases and/or pathological findings (e.g. stenoses), which might interfere with pharmacokinetics and pharmacodynamics of the study medication subjects with existing dysfunction in regulation of glucose metabolism, e.g. deficiency of glucose-6-phosphate dehydrogenase (Glc-6-P DHG) and/ or pathological findings subjects with alcohol and/ or drug dependence and a alcohol consumption more than 20 g alcohol/ day excessive smoking (more than 10 cigarettes or equivalents/ day) subjects with positive finding of HBsAG, HIV and/ or drugs subjects being on a diet (inclusive special or uniform nutritional habits, e.g. vegetarians or undercaloric diet) strong coffee and/ or tea consumption (≥ 1 liter a day) subjects suspected or known not to follow instructions subjects who are unable to understand written and verbal instructions, in particular regarding the risks and inconveniences they will be exposed to as a result of their participation in the study subjects liable to orthostatic dysregulation, fainting, or blackout subjects who took part in other clinical trials in the last 3 months (blocking time due to another clinical trial with investigational products) acute illness less than 14 d in the past blood donation within the last 3 months any medication within 4 weeks prior to the intended first administration of the study medication which might influence functions of the gastrointestinal tract (e.g. laxatives, metoclopramide, loperamide, antacids, H2-receptor antagonists, proton pump inhibitors, anticholinergics) any other medication within 2 weeks prior to the first administration of the study medication or less than 10-time the half-live of the respective drug intake of grapefruit containing food or beverages and poppy seeds containing products 14 d prior to the first drug administration until the last blood sampling of the study

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
-----------------
Male

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Basic Science
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: mixed meal<br> | Dietary Supplement: mixed meal<br>* 250 ml Fortimel compact (chocolate)<br>|
| Active Comparator: mixed meal 2 h after single dose rifampin (600 mg)<br> | Dietary Supplement: mixed meal<br>* 250 ml Fortimel compact (chocolate)<br>Drug: Rifampin<br>* oral rifampin administration (600 mg EREMFAT®)<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| CCK-8 | Cholecystokinin amino acid 8 concentration in blood plasma | 3 h 15 min up to 2 h 15 min before and 5, 10, 15, 20, 25, 30, 45 min, 1, 1.25, 1.5, 2, 3, 4 h after mixed meal | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| GLP-1 | Glucagon-like peptide-1 concentration in blood plasma | 3 h 15 min up to 2 h 15 min before and 5, 10, 15, 20, 25, 30, 45 min, 1, 1.25, 1.5, 2, 3, 4 h after mixed meal | 
| GIP | Gastric inhibitory polypeptide concentration in blood plasma | 3 h 15 min up to 2 h 15 min before and 5, 10, 15, 20, 25, 30, 45 min, 1, 1.25, 1.5, 2, 3, 4 h after mixed meal | 
| glucagon | glucagon concentration in blood plasma | 3 h 15 min up to 2 h 15 min before and 5, 10, 15, 20, 25, 30, 45 min, 1, 1.25, 1.5, 2, 3, 4 h after mixed meal | 
| glucose | glucose concentration in blood plasma | 3 h 15 min up to 2 h 15 min before and 15, 30, 45 min, 1, 1.25 h after mixed meal | 
| potassium | potassium concentration in blood plasma | 3 h 15 min up to 2 h 15 min before and 15, 30, 45 min, 1, 1.25 h after mixed meal | 
| C-peptide | connecting peptide concentration in blood plasma | 3 h 15 min up to 2 h 15 min before and 15, 30, 45 min, 1, 1.25 h after mixed meal | 
| insulin | insulin concentration in blood plasma | 3 h 15 min up to 2 h 15 min before and 15, 30, 45 min, 1, 1.25 h after mixed meal |