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

NCT02515526 | Completed DMC

• 1 other identifier: EtOH_CYP_2013_KPUK
• Study Type: interventional
• Target: 16
• Locations: 1 country
• Sites: 1

Brief Summary

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

Conditions

AOD Effects and Consequences

Outcome Measures

Primary Outcomes (9)

• 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 Outcomes (7)

• 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

Study Arms (2)

Reference

ACTIVE COMPARATOR

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

Test

EXPERIMENTAL

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

Interventions

caffeine, tolbutamide, omeprazole, dextromethorphan, digoxin, midazolam single doses DRUG

Reference period

Also known as: Percoffedrinol, Tolbutamide PCH, Omepazol Ratiopharm, Hustenstiller Ratiopharm, Digacin and Midazolam-ratiopharm

Reference

ethanol multiple doses plus caffeine, tolbutamide, omeprazole, dextromethorphan, digoxin, midazolam single doses DRUG

Test period

Also known as: Percoffedrinol, Tolbutamide PCH, Omepazol Ratiopharm, Hustenstiller Ratiopharm, Digacin, Midazolam-ratiopharm and Wodka Gorbatschow 50%

Test

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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.

You may not qualify if:

• 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)

Sponsors & Collaborators

• University of Cologne: lead
• Umm Al-Qura University: collaborator

Study Sites (1)

Department of Pharmacology I, University Hospital Cologne

Cologne, North Rhine-Westphalia, 50931, Germany

Location

Related Publications (1)

• Hsin CH, Stoffel MS, Gazzaz M, Schaeffeler E, Schwab M, Fuhr U, Taubert M. Combinations of common SNPs of the transporter gene ABCB1 influence apparent bioavailability, but not renal elimination of oral digoxin. Sci Rep. 2020 Jul 27;10(1):12457. doi: 10.1038/s41598-020-69326-y.

  PMID: 32719417 DERIVED

MeSH Terms

Interventions

Caffeine; Tolbutamide; Omeprazole; Dextromethorphan; Digoxin; Midazolam

Intervention Hierarchy (Ancestors)

Xanthines; Alkaloids; Heterocyclic Compounds; Purinones; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Benzenesulfonamides; Sulfonamides; Amides; Organic Chemicals; Sulfonylurea Compounds; Urea; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Sulfones; Sulfur Compounds; 2-Pyridinylmethylsulfinylbenzimidazoles; Sulfoxides; Pyridines; Heterocyclic Compounds, 1-Ring; Benzimidazoles; Morphinans; Opiate Alkaloids; Heterocyclic Compounds, Bridged-Ring; Heterocyclic Compounds, 4 or More Rings; Phenanthrenes; Polycyclic Aromatic Hydrocarbons; Polycyclic Compounds; Digitalis Glycosides; Cardenolides; Cardiac Glycosides; Cardanolides; Steroids; Fused-Ring Compounds; Glycosides; Carbohydrates; Benzodiazepines; Benzazepines

Study Officials

• Uwe Fuhr

  Department of Pharmacology,University Hospital Cologne

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: OTHER
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Prof. Dr. Uwe Fuhr

Study Record Dates

• First Submitted: August 1, 2015
• First Posted: August 4, 2015
• Study Start: June 1, 2015
• Primary Completion: August 27, 2015
• Study Completion: August 27, 2015
• Last Updated: September 9, 2019

Record last verified: 2019-09

Locations

DE (1)