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Clinical Pharmacokinetics of Small Doses of Ethanol: Role of Gastric Emptying and Other Influences in the Upper Gastrointestinal Tract
Linköping University, Department of Medicine and Care, Internal Medicine. Linköping University, Faculty of Health Sciences.
2001 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis deals with the clinical pharmacokinetics of small doses of ethanol as influenced by conditions in the proximal gut. The bioavailability of orally administered ethanol depends to a large extent on gastric emptying, which is influenced by pre-treatment with drugs and other clinically relevant factors in the upper gastrointestinal tract.

The impact of the relative amount of carbohydrate, fat or protein in a test meal on the pharmacokinetics of a small dose of ethanol was studied in nine healthy male subjects. Drinking ethanol after eating a meal was compared with intake of the same dose consumed on an empty stomach or given intravenously. The peak blood alcohol concentration (BAC) and the area under the curve (AUC) were greatest when ethanol was given intravenously (100% availability). Drinking ethanol after a meal resulted in considerably lower peak BAC and AUC compared with drinking on an empty stomach. However, the macronutrient composition of the meal had no significant effect on the pharmacokinetics of ethanol as reflected in almost identical blood alcohol curves after high-fat, high-protein, or high-carbohydrate meals.

The decreased bioavailability of ethanol after oral administration compared to intravenous infusion of the same dose can be explained by a first-pass metabolism (FPM). Some investigators attribute this FPM to the presence of alcohol dehydrogenase (ADH) in the gastric mucosa. Gastric ADH activity was studied in mucosal biopsies from 76 patients referred for upper gastrointestinal endoscopy. Those patients (n = 36) infected with H. pylori received treatment to eradicate the bacterium and repeat biopsies were obtained 2 months and one year later. There were no significant differences in gastric ADH activity between males and females and between different age groups. Gastric ADH activity was significantly decreased in the antrum among patients with H. pylori infection. After eradication of H. pylori, gastric ADH activity in the antrum was normalised within two months. No significant differences in the ADH activity were found in biopsies from the corpus. Histological examination of gastric biopsies showed that those exhibiting the most pronounced inflammation and histologic changes had significantly lower ADH activity compared with biopsies judged to have normal histology.

Several drugs inhibit gastric ADH in vitro. Among them acetylsalicylic acid (ASA) was suggested to increase the bioavailability of orally administered ethanol. We studied the effect of low-dose ASA on the pharmacokinetics of a small dose of ethanol in 10 healthy men. Low-dose ASA (75 mg) decreased significantly the peak BAC and the time to reach peak BAC was also prolonged. The underlying mechanism appears to be delayed gastric emptying which was assessed by the paracetamol absorption test. To evaluate the effect of accelerating gastric emptying on ethanol pharmacokinetics, the prokinetic substance cisapride was given to the same 10 subjects. When ethanol was ingested 60 min after a meal pre-treatment with cisapride significantly increased peak BAC. However, this increase in BAC after cisapride was modest compared with the BAC reached when the same dose of ethanol was ingested on an empty stomach. The corresponding serum paracetamol curves indicated that a faster rate of gastric emptying was the main factor responsible for the differences in ethanol pharmacokinetics.

Analysis of breath alcohol concentration (BrAC) is a practical and non-invasive method to estimate the BAC and this technique is used worldwide for forensic purposes. The reliability of BrAC measurements in subjects with gastroesophageal reflux disease (GERD) has been questioned. We therefore compared simultaneously obtained breath and venous blood alcohol concentrations in 10 patients with severe GERD scheduled for antireflux surgery. In one of the experiments gastroesophageal reflux was provoked by applying abdominal compression. Although some patients complained of pronounced reflux symptoms the breath instrument readings of BrAC did not deviate from the corresponding BAC in the two test situations, that is, with and without provocation of reflux.

This thesis has established that measuring alcohol in breath can be used to monitor blood alcohol concentration also in subjects with severe GERD. The relative amount of fat, carbohydrate, or protein in a test meal does not influence the pharmacokinetics of a small dose of ethanol as long as the caloric contents of the meals are similar. The rate of gastric emptying is a major factor determining the bioavailability of orally administered ethanol. Treatment with low-dose ASA (75 mg) delayed gastric emptying and caused a lowering of the peak BAC. The prokinetic drug cisapride, administered under conditions that resemble clinical use, increased the peak BAC by accelerating gastric emptying. However, the drug-induced increase in BAC was much less than the BAC observed after drinking the same dose of ethanol on an empty stomach. H. pylori infection is associated with decreased antral ADH activity related to gastritis. Eradication of H. pylori normalises antral ADH activity within two months.

Place, publisher, year, edition, pages
Linköping: Linköpings universitet , 2001. , 68 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 682
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-27506Local ID: 12162ISBN: 91-7219-971-7 (print)OAI: oai:DiVA.org:liu-27506DiVA: diva2:248058
Public defence
2001-05-25, Berzeliussalen, Universitetssjukhuset, Linköping, 13:00 (Swedish)
Opponent
Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2012-09-07Bibliographically approved
List of papers
1. Effect of high-fat, high-protein, and high-carbohydrate meals on the pharmacokinetics of a small dose of ethanol
Open this publication in new window or tab >>Effect of high-fat, high-protein, and high-carbohydrate meals on the pharmacokinetics of a small dose of ethanol
1997 (English)In: British Journal of Clinical Pharmacology, ISSN 0306-5251, E-ISSN 1365-2125, Vol. 44, no 6, 521-526 p.Article in journal (Refereed) Published
Abstract [en]

Aims To investigate whether the relative amounts of fat, carbohydrate (CHO), or protein in a meal influence the pharmacokinetics of a small dose of ethanol.

Methods Nine healthy men received ethanol (0.30 g kg−1 body weight) on five occasions in a randomized cross-over fashion. On three occasions the dose of ethanol was consumed within 15 min of eating a standardized breakfast of similar volume and calorific value but containing different amounts of fat, CHO, and protein. On two other occasions the same dose of ethanol was ingested on an empty stomach (overnight fast) or administered by intravenous (i.v.) infusion over 30 min.

Results The blood-ethanol profiles showed large inter and intraindividual variations, especially when ethanol was ingested after eating food. The peak blood-alcohol concentrations (BAC) were 16.6±4.0, 17.7±7.1, and 13.3±4.0 mg dl−1 (mean±s.d.) after fat, CHO, and protein-rich meals and 30.8±4.3 and 54.3±6.4 mg dl−1 after fasting and i.v. infusion, respectively. The corresponding areas under the concentration-time profiles (AUC) were 1767±549, 1619±760, 1270±406 mg dl−1 min after fat, CHO, and protein-rich meals compared with 3210±527 and 4786±446 mg dl−1  min after fasting and i.v. infusion, respectively. The time required to eliminate ethanol from the blood was shortened by 1–2 h in the fed-state.

Conclusions Drinking ethanol after eating a meal, regardless of the nutritional composition, decreases the systemic availability of ethanol. Because gastric emptying is slow and more prolonged with food in the stomach, the delivery of ethanol to the duodenum and the liver will be highly variable as will the hepatic clearance of ethanol. Provided that portal venous BAC remains fairly low and ethanol metabolizing enzymes are not fully saturated then part of the dose of ethanol can be cleared by hepatic first-pass metabolism (FPM), as one consequence of Michaelis-Menten elimination kinetics.

Place, publisher, year, edition, pages
Blackwell Publishing Ltd, 1997
Keyword
bioavailability, blood ethanol, first-pass metabolism, food, liver blood flow, macronutrients, pharmacokinetics
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-59761 (URN)71214900001 ()
Available from: 2010-09-27 Created: 2010-09-24 Last updated: 2017-12-12Bibliographically approved
2. Low-dose aspirin decreases blood alcohol concentrations by delaying gastric emptying
Open this publication in new window or tab >>Low-dose aspirin decreases blood alcohol concentrations by delaying gastric emptying
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1997 (English)In: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 53, no 04-Mar, 241-246 p.Article in journal (Refereed) Published
Abstract [en]

Objective: To determine if treatment with low-dose aspirin (ASA) influences the bioavailability of orally administered alcohol and to assess whether this is caused by altered gastric emptying as measured by the paracetamol absorption test.

Methods: In a single-center controlled crossover trial, ten healthy male medical students, aged 20–27 years, participated in two experiments in random order. Both times they took paracetamol (1.5 g together with a standardized breakfast) and drank ethanol (0.3 g/kg) 1 h after eating breakfast. On one drinking occasion, no previous medication was given. The other alcohol session was performed after the subjects had taken 75 mg ASA once daily for 7 days. On both occasions, venous blood samples were obtained at exactly timed intervals for a period of 3.5 h.

Results: The blood-ethanol profiles showed large interindividual variations for both experiments. After treatment with ASA, the maximum blood-ethanol concentration was distinctly lower in seven subjects, almost unchanged in two subjects and increased in one subject. Overall, a statistically significant decrease in the peak blood-ethanol concentration was observed. The time required to reach peak blood-ethanol levels was somewhat longer after treatment with ASA. Although the areas under the concentration–time profiles were smaller after ASA treatment, these differences were not statistically significant. The concentrations of paracetamol in plasma were lower when ethanol was ingested after treatment with ASA and the areas under the concentration–time curves (0–170 min) were smaller.

Conclusions: Intake of low-dose ASA (75 mg daily) tends to delay the absorption of a moderate dose of ethanol, which results in lower peak blood-ethanol concentrations and smaller areas under the concentration–time curves. The underlying mechanism seems to be delayed gastric emptying as indicated by the paracetamol absorption test.

Place, publisher, year, edition, pages
Springer Science Business Media, 1997
Keyword
Ethanol - Low-dose aspirin
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-59760 (URN)10.1007/s002280050369 (DOI)71436600013 ()9476038 (PubMedID)
Available from: 2010-09-27 Created: 2010-09-24 Last updated: 2017-12-12Bibliographically approved
3. Impact of gastric emptying on the pharmacokinetics of ethanol as influenced by cisapride
Open this publication in new window or tab >>Impact of gastric emptying on the pharmacokinetics of ethanol as influenced by cisapride
1999 (English)In: British Journal of Clinical Pharmacology, ISSN 0306-5251, E-ISSN 1365-2125, Vol. 48, no 5, 728-732 p.Article in journal (Refereed) Published
Abstract [en]

Aims To examine the influence of cisapride on the pharmacokinetics of ethanol and the impact of gastric emptying monitored by the paracetamol absorption test.

Methods Ten healthy male volunteers took part in a cross-over design experiment. They drank a moderate dose of ethanol 0.30 g kg−1 body weight exactly 1 h after eating breakfast either without any prior drug treatment or after taking cisapride (10 mg three times daily) for 4 consecutive days. In a separate study, the same dose of ethanol was ingested on an empty stomach (overnight fast). Paracetamol (1.5 g) was administered before consumption of ethanol to monitor gastric emptying. Venous blood was obtained at 5–10 min intervals for determination of ethanol by headspace gas chromatography and paracetamol was analysed in serum by high performance liquid chromatography (h.p.l.c.).

Results The maximum blood-ethanol concentration (Cmax ) increased from 3.8±1.7 to 5.6±2.3 mmol l−1 (±s.d.) after treatment with cisapride (95% confidence interval CI on mean difference 0.28–3.28 mmol l−1 ). The area under the blood-ethanol curve (AUC) increased from 6.3±3.5 to 7.9±2.6 mmol l−1 h after cisapride (95% CI −0.74–3.9 mmol l−1 h). The mean blood ethanol curves in the cisapride and no-drug sessions converged at ≈2 h after the start of drinking. Both Cmax and AUC were highest when the ethanol was ingested on an empty stomach (Cmax 9.5±1.7 mmol l−1 and AUC 14.6±1.9 mmol l−1 h), compared with drinking 1 h after a meal and regardless of pretreatment with cisapride.

Conclusions A small but statistically significant increase in Cmax occurred after treatment with cisapride owing to faster gastric emptying rate as shown by the paracetamol absorption test. However, the rate of absorption of ethanol, as reflected in Cmax and AUC, was greatest after drinking the alcohol on an empty stomach. The cisapride–ethanol interaction probably lacks any clinical or forensic significance.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-25121 (URN)10.1046/j.1365-2125.1999.00080.x (DOI)9554 (Local ID)9554 (Archive number)9554 (OAI)
Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2012-09-07Bibliographically approved
4. Reliability of breath-alcohol analysis in individuals with gastroesophageal reflux disease
Open this publication in new window or tab >>Reliability of breath-alcohol analysis in individuals with gastroesophageal reflux disease
Show others...
1999 (English)In: Journal of Forensic Sciences, ISSN 0022-1198, E-ISSN 1556-4029, Vol. 44, no 4, 814-818 p.Article in journal (Refereed) Published
Abstract [en]

Gastroesophageal reflux disease (GERD) is widespread in the population among all age groups and in both sexes. The reliability of breath alcohol analysis in subjects suffering from GERD is unknown. We investigated the relationship between breath-alcohol concentration (BrAC) and blood-alcohol concentration (BAC) in 5 male and 5 female subjects all suffering from severe gastroesophageal reflux disease and scheduled for antireflux surgery. Each subject served in two experiments in random order about 1-2 weeks apart. Both times they drank the same dose of ethanol (~0.3 g/kg) as either beer, white wine, or vodka mixed with orange juice before venous blood and end-expired breath samples were obtained at 5-10 min intervals for 4 h. Ah attempt was made to provoke gastroesophageal reflux in one of the drinking experiments by applying an abdominal compression belt, Blood-ethanol concentration was determined by headspace gas chromatography and breath-ethanol was measured with an electrochemical instrument (Alcolmeter SD-400) of a quantitative infrared analyzer (Data-Master). During the absorption of alcohol, which occurred during the first 90 min after the start of drinking, BrAC (mg/210 L) tended to be the same of higher than venous BAC (mg/dL). In the post-peak phase, the BAC al ways exceeded BrAC. Four of the 10 subjects definitely experienced gastric reflux during the study although this did not result in widely deviant BrAC readings compared with BAC when sampling occurred at 5- min intervals. We conclude that the risk of alcohol erupting from the stomach into the mouth owing to gastric reflux and falsely increasing the result of an evidential breath-alcohol test is highly improbable.

Keyword
forensic science, alcohol, analysis, blood, breath analysis, disease state, drinking and driving, DUI challenges, gastric reflux
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-25022 (URN)10432616 (PubMedID)9443 (Local ID)9443 (Archive number)9443 (OAI)
Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2012-09-07Bibliographically approved
5. Influence of Age, Sex, and Helicobacter pylori Infection Before and After Eradication on Gastric Alcohol Dehydrogenase Activity
Open this publication in new window or tab >>Influence of Age, Sex, and Helicobacter pylori Infection Before and After Eradication on Gastric Alcohol Dehydrogenase Activity
2001 (English)In: Alcoholism: Clinical and Experimental Research, ISSN 0145-6008, E-ISSN 1530-0277, Vol. 25, no 4, 508-512 p.Article in journal (Refereed) Published
Abstract [en]

Background: Gastric alcohol dehydrogenase may contribute to the metabolism of orally ingested ethanol and decrease the bioavailability of the drug. The aims of this study were to assess the impact of Helicobacter pylori infection and its eradication on gastric alcohol dehydrogenase activity and to relate the findings to gastric histology. Furthermore, the role of age- and sex-related differences in gastric alcohol dehydrogenase activity were studied.

Methods: A total of 76 subjects (39 women and 37 men) underwent upper gastrointestinal endoscopy, and biopsies were obtained from the corpus and antrum. The specimens were used for determining gastric alcohol dehydrogenase activity, histological examination, and urease testing. Subjects with H. pylori infection (n= 36) received medication to eradicate the infection, and repeat biopsies were taken 2 and 12 months later.

Results: No significant difference in gastric alcohol dehydrogenase activity was found between men and women (p > 0.05). Gastric alcohol dehydrogenase activity did not differ significantly between the subjects older than 50 years (n= 39) and those 50 years or younger (n= 37). In subjects with H. pylori infection, gastric alcohol dehydrogenase activity was significantly reduced in the antrum (p < 0.05). After eradication of H. pylori, alcohol dehydrogenase activity in the antrum increased significantly within 2 months (p < 0.01). Antral biopsies with the most pronounced inflammation and histological changes had significantly decreased alcohol dehydrogenase activity (p < 0.05). In contrast, no significant differences were found in corpus.

Conclusions: H. pylori infection is associated with decreased antral alcohol dehydrogenase activity, which seems to be related to the severity of the inflammatory changes in the mucosa. Eradication of H. pylori normalizes antral alcohol dehydrogenase activity within 2 months.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-24960 (URN)10.1111/j.1530-0277.2001.tb02243.x (DOI)9371 (Local ID)9371 (Archive number)9371 (OAI)
Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2012-09-07Bibliographically approved

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