Alcohol Inhibits Drug Metabolism by Carboxylesterases

Overview

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.

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.

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