Does Alcohol Able to Change Pharmacokinetics of Drugs in Alcoholic People?

Received: 10-Dec-2021;Accepted Date: Dec 24, 2021; Published: 31-Dec-2021

Abstract

Introduction: Alcohol is a common drink in the world that its consumption increases after chronic drinking because of addiction; the harmful usage of this drink can cause the fatal injuries exactly on brain and heart and exactly can affect the body enzymes and so the drugs pharmacokinetics, and can reduce or increase the effectiveness of the drugs; these changes can cause by many reasons like changing the drugs absorption, distribution, metabolism or excretion and elimination. Using ethanol (EA) along with medications can cause the changes in alcohol metabolism too so it may cause the alcohol toxicity. The aim of the current study is to review the recent available data about these topics to discuss about the ethanol-drugs reaction.

Methods: The process of writing this article was started by searching the related articles in “Pubmed”, “Googlescholar”, “Sciencedirect” and “Elsevier” and choosing the best and most content of them, then these articles were investigated and summarized, at the end the extracted contents were classified into several sections and presented as follows.

Results: The review of many important articles and summarizing them was shown that ethanol causes exact changes in drug pharmacokinetics and sometimes in diseases therapeutic processes and sometimes these effects complicates the patient’s condition and even chronic alcohol usage can cause some diseases itself; it should say that using ethanol in drug dosages can have good effects in drug absorbance in oral and local usages. At the end it should say that using some of drugs with alcohol can change its pharmacokinetic in good or bad position, so using drugs with ethanol should checkout from all dimensions.

Conclusion: Chronic usage of alcohol as a daily drink makes serious body damages because of the changes in liver enzymes, gastric drug absorbance, kidneys function and etc. so alcohol necessarily damages the life (in healthy people it induces many kinds of diseases and in drug usage patients it makes the treatment process difficult).

Introduction

Ethanol (Alcohol) is a chemical compound with the chemical formula C₂H₆O; this is a volatile, flammable, colorless liquid witch is naturally produced by the fermentation of sugars by yeasts or synthetic via petrochemical processes [1,2]. It also has medical, chemical and antidotal (ethanol may be administered as an antidote to methanol and ethylene glycol poisoning) uses but ethanol today is use as a drink and unfortunately using the alcohol as a daily drink is widespread in many countries of the world and starting to use it from a young age can cause the damages to body organs and physical weakness [3-11]. But most importantly and according to the subject discussed in this article, the chronic alcohol consumption can cause many changes in drugs pharmacokinetics by changing in liver enzymes, stomach acidity and intestinal membrane permeability [12]. These changes can be good or bad; concomitant use of this drink with some of medications can change the ethanol metabolism to and cause toxication [13]. This article is discussed about some of the drug–alcohol interactions and tries to briefly describe these interacts.

Effects of Ethanol on Drugs Pharmacokinetics

Pharmacokinetics describes how the body affects a specific drug or chemical after entering the body through the mechanisms of absorption, distribution, metabolism and the excretion (ADME); changing each of these steps can cause irreparable complications on the patient (Figure 1) [14].

Figure 1: Steps of drugs Pharmacokinetics.

Absorption

Drug absorption is the movement of a drug from its place of administration into the blood stream that is controlled by drugs solubility, dissolution rate, and intestinal permeability [15]. This process can change by many different reasons like using surfactants with drugs, foods effect on drugs absorption and effects of alcohol on drugs absorption [12,16-18].

In vitro dissolution test of extended release (ER) oxymorphone was shown that dissolution of the drug become slower when the alcohol concentration was increased in the environment (exactly in more than 40% of ethanol concentration) and the lowest dissolution rate was shown in highest alcohol concentration; these results were also observed for crush-resistant (CR) oxymorphone; In vivo evaluation was studied by enrolling the healthy volunteers, this evaluation was shown that increasing the plasma ethanol concentration can cause the increasing in maximum concentration (≈14%) and AUC (Area Under the Curve) (≈18%) of oxymorphone in both of ER and CR tablets recipients [19]. Trans-resveratrol (a type of natural phenols that is produced by several plants when they are attacked by pathogens or as a response for injuries) is another drug that was checked on eight healthy subjects that used 100 ml of 5% ethanol to swallow their drug (trans-resveratrol 2000 mg) each time they gave it [20]. The research was stated that using the drug with the said volume of ethanol can increase the drugs Cmax in compare with this parameter of the drug when it was used after the standardized breakfast (a breakfast with approximately 500 calories, 18 g fat, 70 g carbohydrates and 12 g proteins), high fat breakfast (approximately 750 calories; 45 g of fat, 60 g of carbohydrates and 30 g of proteins) and with 500 mg of quercetin, this increasing can be observed in AUC too (except of using resveratrol after high fat breakfast that was shown higher AUC compared to ethanol-resveratrol) [21]. Another study on the healthy adults between 21-45 years of age which are able to tolerate the alcohol shown that using ethanol in the 4%, 20%, and 40% of concentration with a single 18.8 mg dose of AMP XR-ODT can have no exact effects on Cmax, Tmax, or the overall shape of the concentration– time curve for d- and l-AMP compared with administration of AMP XR-ODT with water (AMP XR-ODT=Extended- Release Orally Disintegrating Tablet Formulation of Amphetamine); it should say that d and l refers to the chiral circulation of the drug molecules [22]. In this study 14 volunteers between 22-42 years old were tested to check the effects of ethanol on Methylphenidate (MPH) absorption; one hour prior to dosing, the subjects consumed a light breakfast that is finished over a period of 10 minutes; then the drug was administered with 240 mL of room temperature water; depending on the randomization assignment, an ethanol or non-ethanol orange juice drink was consumed 4.0 to 4.25 hours after MPH dosing (for alcohol free treatments, the alcohol volume was replaced with water). They were received a standard lunch after the 3.25 to 3.75 hour period and a standardized dinner 10.5 hours after MPH dosing; the effects of the ethanol on the absorption of MPH is about 4.4% after 1.5 and 30.4% after 6 hours of drug dosing, alcohol increased the drug absorption in compare with non-alcoholic treatments [23]. Another similar study was showed the results that were confirming the implicated data adding alcohol to local products can enhance the drug absorbance in this drugs, study on Yucatan micropig skin (YMP) shows that adding ethanol to HBM (p-hydroxyl benzoic acid methyl ester) causes increasing in its skin permeation and skin concentration up to 300% [24]. This caused because of enhancing the drug penetration and inhibiting and decreasing the drug hydrolysis in skin environment (YMP was selected in this study because of its high resemblance to human skin) [25]. The main cause of low aqueous solubility of some of drugs is poor hydration as a consequence of high lipophilicity but the concomitant intake of ethanol can affect the bioavailability of several available drug products by the reasons like rapid drug dissolution and increasing the rate of drug absorption; a research on the ethanol effects on the solubility and absorbance of Indomethacin and Felodipine demonstrated that it can increase the solution of the mentioned drugs in both gastric and intestinal environments and the absorbance of the Indomethacin and Felodipine too (the maximum plasma concentration (MPC) of Felodipine was increased up to 50% and MPC of Indomethacin was increased about 40% with concomitant intake of alcohol) (Table 1) [26]. Another similar research was showed that the use of ethanol cause the increasing of the solution of low soluble drugs like Griseofulvin, felodipine, Cinnarizine, Terfenadine and other in the NaCl solution (in vitro) and gastric fluid (in vivo), the increasing of the drugs absorption was documented in this research too [27].

Table 1: Effect of 20% of Ethanol on apparent solubility in gastrointestinal fluids of rats. (FaSSGF=fasted state simulated gastric fluid; rFaSSIF=rat fastedstate simulated intestinal fluids)[26].

Distribution

Drug distribution can be defined as the movement of drug between blood and extravascular tissues; as drug absorption occurs, drug transfers to the blood and then takes to the organ; in most cases, the process of drug distribution is passive and don’t need any input of energy, but sometimes this process becomes active (like receptor mediated endocytosis and carrier mediated active transport) and needs to use energy that also play important roles in either increasing or limiting the extent of drug distribution this step is one of the most important parts of drugs pharmacokinetics for their correct prescription [28-30]. Researches had shown that using alcohol cannot effect the drugs distribution significantly because the interaction between ethanol and plasma proteins is not extensively enough to affect drugs distribution [31].

Metabolism

Drug metabolism can be introduced as a coordinated process that drugs are metabolized and disposed through that, can considered as a process that is done by trillions of microorganisms residing in the human gastrointestinal tract or can be the interaction of the drug and other molecules From the moment of use until the effect [32,33]. These processes can affected by smoking, increasing and decreasing of renal and liver enzymes, increasing of blood urea and etc. but in this article the effects of alcohol on drugs metabolism and mechanisms of the effects will be discussed [34].

A test on homogenized skin of Yucatan micropig (YMP) to check HBM metabolism, with and without alcohol, was shown the formation rate of HBA was decreased by about 50% when ethanol was added but instead, the formation of p-hydroxy benzoic acid ethyl ester occurred at approximately twice the rate of the hydrolysis of HBM without alcohol [25]. Another research on methylphenidate (Ritalin ®) demonstrated that ethanol can cause the increasing in blood concentration of the drug because of esterase inhibition in liver and it may influence pleasurable effects of the drug and this in turn can cause additional abuse liability and addiction; also simultaneous use of alcohol and Ritalin can increase the drug absorption rate too [35]. Charles W. Flexner and his colleagues demonstrated that alcohol consumption can increase CYP3A4 activity (a process can be intensified in mixture of ethanol and isopentanol (most of alcoholic beverages containing the mixture of these two alcohols)), this can cause the reduction of HIV protease inhibitors or nonnucleoside reverse transcriptase inhibitors witch are metabolized by CYP3A4 and reducing the therapeutic effect of these drugs in the patients who are using alcohol and HIV drugs simultaneously and following that, increasing the duration of treatment in these patients using EA can affect the drug metabolism enzymes in macrophages [34,36]. For an example, using alcohol can cause the significant changes in enzymes of U937 macrophages by effecting the mRNA and protein expressions (exactly CYP2D6) and so changing the metabolism of the specific drugs (Table 2) [37]. Although some of studies and researches shows that alcohol cant effect some of other enzymes like CYP2C and P-glycoprotein and the changing in some enzymes amount by continuous alcohol consumption can effect in other enzymes effect and function themselves [38]. For example when alcohol causes increasing in CYP2E1 enzymes in liver followed by this the metabolism of many of drugs and substrates will increase because of the CYP3A4 enzymes increasing that is caused by the effect of 2E1 on 3A4 [39]. Carboxylesterase is one of phase I drug metabolizing enzymes that can found in brain, gastrointestinal tract and exactly in liver, this enzyme plays an important role in pharmacokinetic and biotransformation of prodrugs and can play a role as a strong scavenger toward the highly toxic organophosphorus agents [40-42]. Alcohol can affect the enzyme function by decreasing the power of that in some of drugs like oseltamivir by inhibiting the change of the drug to its active metabolite (oseltamivir-carboxylate) and increasing the (AUC)_0^6 of oseltamivir itself and decreasing the same parameter for active metabolite (it should say that the half-life, tmax and Cmax of both drug and active metabolite don’t change significant in alcohol administration); but in salicylic acid (Aspirin®) EA can’t effect the metabolism and other pharmacokinetical parameters [43]. Low to moderate doses of alcohol can cause the significant reduction in cerebral glucose metabolism and moreover, in alcoholics it showed much than in healthy controls; to prove the subject, in a test, the participants drank the alcohol with the dose of 0.75 g/kg and then their alcohol blood concentration was checked in specific time intervals and the metabolism of glucose was checked by using the PETscan, the results showed that acute alcohol administration decreased whole brain glucose metabolism during intoxication (the decreases were larger in the cerebellum and occipital cortex, and smaller in the thalamus and striatum) [44]. alcoholic liver diseases are the kinds of chronic diseases that are seen at the alcohol abused persons, one of the most important complications of these diseases are disorders of lipids metabolism, for example ethanol can affect the fatty acids and triglyceride synthesis by causing insulin resistance and followed by decreasing the hepatic concentration of glucose, one other of most important effects of ethanol on lipid based cycles of the liver and exactly the body, is disrupting the correct process of carnitine receiving process and its circulation [45]. Smoking and using alcohol are two causes of premature death especially when consumed together because ethanol can cause the exact decreasing in nicotine metabolism; studies have shown that the cessation of using alcohol in smokers causing the significant changes in urine excreted nicotine metabolites for example the urine concentration of Nicotine N’Oxide at the tests baseline is 621 ng/mg and is 1155 ng/mg at the seventh week after alcohol drinking stop but the most notable metabolite in urine is nicotine itself that was changed up to 1960 ng/mg after 7 weeks [46].

Table 2: Effect of 100 mM of Ethanol on RNA and protein expression in U937 macrophages [37].

Elimination

Elimination of a drug is known as drug metabolism (with liver, as the most exact metabolizer in the body, and some other organs like skin, lungs and some of glands) and drug excretion with the kidneys; studying the elimination is done by using some of parameters like drugs half-life and its clearance [47]. No data were found to confirm or reject the effect of alcohol on drugs pharmacokinetics.

Effects of Drugs on Ethanol’s Pharmacokinetic

Alcohol is metabolized by cytochrome P450 type 2E1 and alcohol dehydrogenase (ADH); so the drugs which can inhibit the above mentioned enzymes would lead to a clinically significant pharmacokinetic interaction with ethanol, which include only a limited number of drugs [48].

Discussion

An article was checked the effects of Aspirin, Salicylate, Acetaminophen and Cimetidine on ethanol’s pharmacokinetic, the data was showed that all of these drugs can inhibit the hepatic metabolism of EA by inhibiting the ADH; Acetaminophen and Salicylate effects appeared modest (about 6.5%-16%) but the effects of Aspirin and Cimetidine were appeared negligible (3%-7% for Aspirin and 0.31%-0.33% for cimetidine); it should said that the difference between the inhibitory power of drugs refers to the isozymes that they are inhibiting in liver (for example Acetaminophen and Salicylate can inhibit the ADH1B^*1/^*1 (specific ADH enzyme that metabolizing ethanol) so more than Aspirin and Cimetidine); all of these effects can increase the blood concentration and half-life of ethanol in human body [49]. H2 blockers (like cimetidine that was discussed) can inhibit the gastric ADH (the much inhibitor in this group is cimetidine because of similarity between its imidazole ring and pyrazole (classical ADH inhibitor) and the less active inhibitor is famotidine). That it can decrease the first pass metabolism of alcohol and so increase the blood alcohol concentration. These changes are more easily detectable by the low doses of alcohol usage [50]. Using some of drugs can decrease the gastric alcohol-induced injuries and inflammations for example using Astragaloside in Intravascular (IV) form causes decreasing in gastric mucosal inflammation because of suppression of neutrophils (which causes mucosal damages and injuries) and reducing the inflammatory factors like ILs and TNF-α [51].

Conclusion

Analyzing many articles proves that the ethanol can affect many of drugs pharmacokinetic by causing good or bad changes in bodies different functions like liver enzymes, skin structure and etc. using alcohol as a chronic drink exactly causes bad changes and sometimes disrupts the treatment process of some of diseases because of the damages that it makes for the drug/drugs that is/are used in that process or exacerbation of the disease by alcohol usage (Both of these together can create complicated situations). But at the same time ethanol in some of dosages can cause increasing in drug absorbance and drug concentration (It means the use of alcohol industrially and in the structure of medicine). It is necessary to mention that in return some of drugs effects alcohol pharmacokinetic and its adverse effects (these effects can be good or bad and it refers to the kinds and extents of the changes).

Acknowledgements

We are grateful to all people who helped us in writing this article, especially Dr. Solmaz Asnaashari for her constructive help in planning the process of writing this article.

Conflict of Interests

None declared.

Funding Sources

All the costs, tools, and necessary facilities for writing this article were provided by the authors themselves.

Author's Contributions

Both of authors were involved in all stages of the article writing process.

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