Alcohol Inhibits Drug Metabolism by Carboxylesterases
Condition: Drug Interactions
Study type: Interventional
Phase: Phase 1

Summary: 
      The purpose of this study is to determine if alcohol is able the affect the body's ability to
      eliminate two commonly used medication, oseltamivir and aspirin. We hypothesize that drinking
      alcohol may reduce the body's ability to break down these two medications along with many
      others.This could affect the amount of drug in the blood which could impact how well these
      drugs work and whether patients have side effects.
    

Detailed description: 
      Carboxylesterases are enzymes that metabolize a growing number of commonly used medications.
      In humans, two carboxylesterases, carboxylesterase-1 (hCE1) and carboxylesterase-2 (hCE2),
      found primarily in the liver and intestine respectively, play an important role in the
      biotransformation of numerous classes of commonly used drugs containing ester groups
      including ACE inhibitors, anticancer agents, opiate analgesics, HMG-CoA reductase inhibitors
      (statins), CNS stimulants, antiviral medications, and antiplatelet agents.

      Factors affecting the activity of carboxylesterases would be expected to markedly alter the
      pharmacokinetics and clinical effects of substrate drugs. One key factor that could affect
      catalytic activity is drug interactions that inhibit carboxylesterase function. The
      importance of inhibition of drug metabolism in medication safety and efficacy is well
      established for drugs that undergo metabolism by cytochrome P450 enzymes. In distinct
      contrast, little is known about the potential for carboxylesterases to serve as a target for
      metabolic inhibition mediated by drug interactions.

      It is well established that ethanol is an inhibitor of cocaine metabolism, a drug that is
      eliminated by carboxylesterase hydrolysis. We propose that the ethanol-mediated inhibition of
      carboxylesterases activity demonstrated with cocaine metabolism will occur with other
      substrate drugs. This has widespread implications because of the large number of drugs that
      are carboxylesterase substrates. In the United States, over 100 million people consume
      ethanol making co-ingestion with carboxylesterase substrate drugs a common occurrence. We
      believe that this is a prevalent drug interaction that is largely overlooked and has not been
      systematically evaluated, but may importantly affect the disposition, safety, and efficacy of
      these medications. To address this gap, we will evaluate the effect of ethanol on the
      disposition of oseltamivir, an hCE1 substrate, and aspirin, an hCE2 substrate, in humans.

      Normal healthy volunteers will report to the University of Tennessee Health Science Center
      Clinical Research Center (CRC) for a 10 hour stay on four separate days and receive each of
      the following treatments in random order:

        1. Oseltamivir (Tamiflu®) 150 mg. Subjects will drink orange juice (about 10 ounces
           although the amount may vary slightly based on weight) over 15 minutes. Fifteen minutes
           after drinking the orange juice, subjects will receive two (2) 75 mg capsules of
           oseltamivir with 5 ounces of water. Blood samples (1 teaspoonful) to determine the
           amount of oseltamivir in blood will be collected before the dose and 0.5, 1.0, 1.5, 2.0,
           3.0, 4.0, 6.0, 8.0, 10, and 24 hours hours after the dose. Subjects will be allowed to
           leave the CRC after the 10 hour blood sample is collected and return the following day
           for the 24 hour sample.

        2. Oseltamivir (Tamiflu®) 150 mg + Ethanol. In this phase, subjects will drink the same
           amount of orange juice over 15 minutes that will now have ethanol (alcohol) added. The
           amount of ethanol that will be added is calculated to achieve a blood alcohol
           concentration of 0.08 g/dl, which is considered to be legally intoxicated. Fifteen
           minutes after drinking the orange juice + ethanol, subjects will receive two (2) 75 mg
           capsules of oseltamivir with 5 ounces of water. Blood samples will be collected at the
           same times as above. An additional blood sample (1 teaspoonful) for determining the
           blood alcohol concentration will be collected 30 minutes after drinking the orange juice
           + ethanol.

        3. Aspirin 650 mg. Subjects will drink orange juice (about 10 ounces although the amount
           may vary slightly based on your weight) over 15 minutes. Fifteen minutes after drinking
           the orange juice, they will take two (2) 325 mg aspirin tablets with 5 oz of water.
           Blood samples to determine the amount of aspirin in the blood will be collected before
           the aspirin dose and at 10, 20, and 30 minutes after the dose and at 1.0, 1.5, 2.0, 2.5,
           3.0, 4.0, 5.0, 6.0, 7.0, and 8.0 hours after the dose.

        4. Aspirin 650 mg + Ethanol. In this phase, subjects will drink the same amount of orange
           juice over 15 minutes that will now have ethanol (alcohol) added. The amount of ethanol
           that will be added is calculated to achieve a blood alcohol concentration of 0.08 g/dl,
           which is considered to be legally intoxicated. Fifteen minutes after drinking the orange
           juice + ethanol, subjects will take two (2) 325 mg aspirin tablets with 5 ounces of
           water. Blood samples (1 teaspoonful) to determine the amount of aspirin in the blood
           will be collected before the aspirin dose and at 10, 20, and 30 minutes after the dose
           and at 1.0, 1.5, 2.0, 2.5, 3.0, 4.0, 5.0, 6.0, 7.0, and 8.0 hours after the dose.
    

Intervention name(s): Placebo; Ethanol; Oseltamivir; Aspirin
Intervention type(s): Drug; Drug; Drug; Drug
Intervention description(s): Orange juice administered 15 minutes before subjects take oseltamivir or aspirin; Ethanol will be mixed with orange juice and subjects will drink the mixture 15 minutes before receiving oseltamivir or aspirin; Oseltamivir 150 mg orally; Aspirin 650 mg orally will be given
Other intervention name(s): Tropicana orange juice; Ethanol plus Tropicana orange juice; Tamiflu
Intervention MeSH terms: Aspirin; Ethanol; Oseltamivir
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: human carboxylesterase-1; human carboxylesterase-2; alcohol; pharmacokinetics