Effect of Acute Ethanol Consumption on The Activity of Major Cytochrome P450 Enzymes, NAT2 and P-glycoprotein

Study Overview
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Brief Summary
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Protocol title: Effect of acute alcohol consumption on the activity of major cytochrome P450 enzymes, NAT2 and P-glycoprotein. Objectives: The study is mainly conducted to evaluate the effect of acute alcohol consumption on the activity of the most important drug metabolising cytochrome P450 enzymes CYP1A2, CYP2C9, CYP2C19, CYP2D6, intestinal CYP3A4, hepatic CYP3A4, NAT2 and on the activity of the drug transporter p-glycoprotein (intestinal and renal). The study should also provide basis for a planned clinical study on interactions caused by chronic alcohol intake. Design: Single center, open-label, two-way, cross-over study with randomly allocated sequences Test-Reference or Reference-Test. The study is not a clinical drug study according to the German Drug Act. Clinical phase: Not applicable Volunteers: 16 healthy male and female subjects are planned for completion in accordance with the protocol, i.e. with evaluable/analysable data for all periods and treatments. Clinical centre: Department of Pharmacology, Clinical Pharmacology Unit (KPH), University of Cologne, Gleueler Str. 24, 50931Köln, Germany

Official Title
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Effect of Acute Ethanol Consumption on The Activity of Major Cytochrome P450 Enzymes, NAT2 and P-glycoprotein

Conditions
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AOD Effects and Consequences

Intervention / Treatment
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* Drug: caffeine, tolbutamide, omeprazole, dextromethorphan, digoxin, midazolam single doses
* Drug: ethanol multiple doses plus caffeine, tolbutamide, omeprazole, dextromethorphan, digoxin, midazolam single doses


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Caucasian Age: 18-55 years Normal body weight: (body mass index 18.5-30 kg/m2) Considered to be healthy on the basis of extensive pre-study screening Willing and capable to confirm written consent prior to enrolment after ample information has been provided. Normal findings in the medical history and physical examination unless the investigator considers an abnormality to be clinically irrelevant (clinically healthy). The inclusion criterion clinically healthy will be determined both by physical examination and clinical-chemical tests which will be done prior to the clinical part of the study Exclusion Criteria: subjects with any relevant clinical abnormality (as based on extensive medical history, physical examination, vital signs and 12-lead ECG) subjects with electrolyte disturbances subjects with any cardiac arrhythmia subjects with a history or evidence of hypertrophic obstructive cardiomyopathy subjects with a history or evidence of stenosis of the gastrointestinal tract subjects a history or evidence of ulcerative colitis subjects a history or evidence of toxic mega colon subjects with a history or evidence of myasthenia gravis subjects with evidence of chronic infections subjects with a history or evidence of bronchial asthma, COPD, pneumonia or other relevant respiratory diseases subjects with acute infections within the last two weeks subjects with a history of any allergic disease with clinical signs including hay fever and drug allergies subjects with suspicion of hypersensitivity to the investigational medications and/or subjects with a history of severe skin reactions subjects with any clinically relevant laboratory abnormality (incl. positive results for hepatitis and HIV serology) subjects receiving any medication within 1 week prior to study start or during the study (exceptions possible upon decision of Principal Investigator, e.g. paracetamol single dose for acute pain or topical acyclovir for herpes labialis) subjects who have taken a drug with a long half-life (> 24 hours) within four weeks before the first trial day subjects who received chronic drug treatment (> 3 days) within eight weeks before the first trial day subjects who participated in a trial with novel investigational medications within the last 8 weeks before the start of the present study subjects who participated in a trial with a registered compound within the last 4 weeks before the start of the present study subjects who donated blood or plasma within the last 4 weeks before the start of the present study actual smokers defined as subjects who smoked any cigarette during the last three months subjects who are known or suspected to be (social) drug dependent, incl. those drinking more than 50 g alcohol per day, those subjects must reduce their consumption to 30 g. subjects with a history of alcohol or recreational drug addiction subjects with positive drug screening tests subjects with a history of any severe disease that might interfere with the study objectives subjects who are not willing or able to abstain from alcohol, other than given as a study medication in the Reference period, methylxanthine-containing beverages and foods, caffeine containing products, papaver containing products and grapefruit flesh / juice starting from 72 hours before admission to the ward for the study until after the post screening tests subjects who adhere to a special diet (e.g. vegetarians) or lifestyle (incl. working at night and extreme physical activities such as competitive sports and weight lifting) that might interfere with the investigation subjects planning elective hospital treatment within one month after last intake of trial medication subjects who are known or suspected not to comply with the study directives and/or known or suspected not to be reliable or trustworthy subjects who are known or suspected not to be capable of understanding and evaluating the information that is given to them as part of the formal information policy (informed consent), in particular regarding the foreseeable risks and discomfort to which they will be exposed. Anticipated problems of successfully placing an indwelling venous catheter at the forearms

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Reference<br>A cocktail of six different test substances to be administered orally followed by an I.V. dose of midzolam | Drug: caffeine, tolbutamide, omeprazole, dextromethorphan, digoxin, midazolam single doses<br>* Reference period<br>* Other names: Percoffedrinol, Tolbutamide PCH, Omepazol Ratiopharm, Hustenstiller Ratiopharm, Digacin and Midazolam-ratiopharm;|
| Experimental: Test<br>A cocktail of six different test substances to be administered orally followed by an I.V. dose of midzolam. In addition, ethanol will be administered at six different time points with of reaching a blood alcohol concentration of 1 per mille to see its effect on the activity of major cytochrome P450 enzymes, NAT-2 and P-glycoprotein. | Drug: ethanol multiple doses plus caffeine, tolbutamide, omeprazole, dextromethorphan, digoxin, midazolam single doses<br>* Test period<br>* Other names: Percoffedrinol, Tolbutamide PCH, Omepazol Ratiopharm, Hustenstiller Ratiopharm, Digacin, Midazolam-ratiopharm and Wodka Gorbatschow 50%;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| CYP1A2: AUC0-t of caffeine in plasma |  | 2 months | 
| NAT2 activity: (AFMU + AAMU) / (AFMU + AAMU + 1X + 1U) |  | 2 months | 
| CYP2C9: AUC0-t of tolbutamide in plasma |  | 2 months | 
| CYP2C19: Molar omeprazole / 5-OH-omepazole AUC0-t ratio |  | 2 months | 
| CYP2D6: Molar dextromethorphan / dextrorphan AUC0-t ratio |  | 2 months | 
| Hepatic CYP3A4: hepatic clearance of midazolam |  | 2 months | 
| Intestinal CYP3A4: intestinal extraction of midazolam |  | 2 months | 
| Intestinal p-glycoprotein: absolute bioavailability of digoxin (calculated as Ae) |  | 2 months | 
| Renal p-glycoprotein: renal secretion of digoxin |  | 2 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| CYP1A2: Molar paraxanthine /caffeine AUC0-t ratio |  | 2 months | 
| CYP2C9: Tolbutamide plasma concentration 24 h post-dose |  | 2 months | 
| CYP2C19: AUC0-t of omeprazole in plasma |  | 2 months | 
| CYP2C19: Molar omeprazole / 5-OH-omepazole plasma concentration ratio |  | 2 months | 
| CYP2D6: AUC0-t of dextromethorphan in plasma |  | 2 months | 
| CYP2D6: Molar dextromethorphan / dextrorphan plasma concentration ratio |  | 2 months | 
| Intestinal p-glycoprotein: digoxin Cmax |  | 2 months |