Hepatitis C, Acarbose and Acetaminophen--A Dangerous Combination? | Hepatitis Central

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Hepatology, January 1999, p. 285-287, Vol. 29, No. 1

Acarbose and AcetaminophenA Dangerous Combination?

Acetaminophen (paracetamol) is one of the safest and most often used drugs against pain and fever. It was first introducedas an antipyretic and analgetic by Van Mering in 1893 but initiallygained only little attention. After 1950, when it had been recognizedthat acetaminophen was a major metabolite of phenacetin and muchsafer than aspirin, the use of acetaminophen increased. As formany drugs introduced at this time, there were no proper preclinicaltoxicity studies, and the risk for hepatotoxicity was not known.Hepatotoxicity of acetaminophen had been described in cats1and rats2 before the first reports of fulminant hepatic failurein humans after ingestion of doses exceeding 10 g appeared.3,4However, more recent reports clearly document that severe acetaminophenhepatotoxicity can occur in some humans ingesting recommendeddoses of this drug (up to 4 g per 24 hours),5-10 suggesting thatdose alone is not the only risk factor for acetaminophenhepatotoxicity.

As illustrated in Fig. 1, formation of glucuronides or sulfates are the most important pathways of acetaminophen metabolism.Under normal conditions, only approximately 5% of the acetaminopheningested is converted via cytochrome P450 (CYP) 2E1 to N-acetyl-p-benzoquinoneimine(NAPQI).11 NAPQI is an extremely reactive compound that bindscovalently to cellular proteins and appears to be responsiblefor most of the toxicity of acetaminophen in liver and kidney.Because NAPQI is usually detoxified by reacting with glutathione,hepatotoxicity of acetaminophen usually appears only after ingestionof large doses (>10 g) that saturate the conjugation reactionsand deplete the hepatic glutathione stores.12,13

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Fig. 1. Metabolism of acetaminophen. Under normal conditions, formation of the acetaminophen glucuronide or sulfate is dominating and 5% or less is oxidized to NAPQI. NAPQI can react with glutathione or can bind to cellular proteins, leading to cell death. After ingestion of a large dose of acetaminophen (>10 g), the conjugation pathways are saturated and high amounts of NAPQI are produced, potentially leading to acute liver and/or kidney failure.

 

In contrast, the mechanisms leading to hepatotoxicity after ingesting regular doses of acetaminophen are not fully understood.Many of the patients described were regular drinkers of alcohol,which is considered to be a risk factor (table 1). Chronic ingestionof alcohol induces CYP2E114 and depletes the hepatic glutathionestores,15 leading to increased production and decreased degradationof NAPQI and eventually to severe liver damage. Interestingly,acute ingestion of alcohol decreases the toxicity of acetaminophen,probably by inducing a shift of nicotinamide adenine dinucleotidephosphate from the cytosol to the mitochondria,16 thereby decreasingthe function of microsomal oxidative metabolism. In humans, thisprotection by acute ingestion of alcohol appears to last for approximately12 hours.17 For a heavy drinker, it can therefore be dangerousto ingest acetaminophen in the morning, after drinking large amountsof alcohol the preceding night.

View This table table 1. Possible Risk Factors For Acetaminophen-Induced Hepatotoxicity at Normal Dosage

 

Similar to ethanol, isoniazid is metabolized by CYP2E1 and acts also as an inducer.18 Although it is well known that high consumption of ethanol is a risk factor for isoniazid-induced hepatotoxicity,19 treatment with isoniazid is not generally recognized as a risk factor for acetaminophen-induced hepatotoxicity.Nevertheless, the administration of acetaminophen in patientsingesting isoniazid should be performed withcaution.

Other clinical states with a high risk of acetaminophen-induced hepatotoxicity include decreased hepatic glutathione storessuch as in malnutrition. Prolonged administration of acetaminophenmay also deplete glutathione. This is suggested by the observationthat most patients suffering from hepatic failure induced by regulardoses of acetaminophen ingested this drug for several days orlonger.5,7,8

A third group of risk factors is characterized by impaired glucuronide formation, which shifts metabolism of acetaminophenin the direction of the formation of NAPQI.20 Fasting is well-knownto be associated with a decrease in the hepatic carbohydrate reserves21and in the activity of enzymes responsible for the productionof uridine diphosphate-glucuronate,22 leading to increased toxicityof acetaminophen in humans. Interestingly, patients with Gilbert’ssyndrome appear to be more sensitive to acetaminophen than healthysubjects,23 which supports this concept. Because the productionof uridine diphosphate-glucuronate and glutathione are both reactionsdepending on the availability of energy in the form of adenosinetriphosphate, it is conceivable that patients with cardiac failurecould have a depletion of these substrates in zone III of theliver lobe, rendering them more sensitive to the toxic effectsof acetaminophen.5

Acarbose is a competitive inhibitor of intestinal alpha-glucosidases, such as maltase and sucrase, which is intended to decreaseabsorption of glucose. Acarbose is therefore used for the treatmentof type II diabetics. The most important side-effect is flatulencecaused by bacterial metabolism of disaccharides in the colon.However, hepatic injury is not uncommon as evidenced by approximately200 such reports in the World Health Organization database inUppsala, Sweden, which represents about one fourth of all sideeffects reported for this drug. Most liver injuries reported arehepatocellular or mixed and only few are cholestatic. In noneof these reports is acetaminophen indicated as a comedication.Because it has been reported that low intake of carbohydratespotentiates toxicity of CCl4 by inducing CYP2E1,24,25 Wanget al.26 studied the important question of whether treatmentwith acarbose is associated with increased expression and activityof CYP2E1 and increased toxicity of acetaminophen and/or CCl4.The results of this study are reported in the current issue ofHEPATOLOGY. Rats were fed up to 16 mg acarbose per day and ingestedwater containing up to 10% alcohol for 3 weeks. Alcohol aloneincreased expression and activity of CYP2E1, and this increasewas potentiated by the addition of acarbose. The potential clinicalsignificance of these in vitro observations was shown by the administrationof CCl4 or acetaminophen to rats treated with alcohol or combinationalcohol/acarbose. Rats pretreated with the combination showeda higher increase of the transaminases compared with rats treatedwith ethanol alone. The investigators concluded that patientstreated with acarbose should be warned against overuse of drugs,such as acetaminophen, which are converted by CYP2E1 to potentiallytoxicmetabolites.

Although the study has been conducted very carefully, several questions remain unanswered. A first question concerns the doseof ethanol and of acarbose used by the authors. The rats ingestedapproximately 14 mL of 10% alcohol and 16 mg acarbose per day,corresponding to approximately 200 g of alcohol and 3 g of acarbosefor a subject of 70 kg. Two hundred grams of alcohol per day isa very large amount, which is ingested only by a small minorityof the population. The dose of acarbose recommended by the manufactureris 150 mg per day at the beginning with an increase to 300 mgor exceptionally to 600 mg per day, depending on the effect andhow well the drug is tolerated. The doses chosen by the investigatorsof both ethanol and acarbose were, therefore, substantially higherthan those that are normally ingested by humansubjects.

A second question concerns the mechanism of action of acarbose. As illustrated in table 1, not only induction of CYP2E1 butalso a decrease in the hepatic content of glutathione and/or glucuronidationcapacity are important risk factors for acetaminophen hepatotoxicity.Because deprivation of carbohydrates, for instance during starvation,is known to decrease hepatic glucuronidation,21,22the possibilitymust be considered that acarbose increases the toxicity of acetaminophenalso by this mechanism. This possibility was not investigatedby Wang etal.

Lastly, increased production of NAPQI may not be the only mechanism mediating the toxic effects of acetaminophen. Recent studiessuggest that some of the toxicity may be caused by increased productionof soluble compounds including interleukin-1, tumor necrosis factor-alpha,reactive oxygen species, and nitric oxide by macrophages and hepatocytes.27,28Therefore, the effect of acarbose on these intermediates shouldalso beinvestigated.

Which advice should be given to a diabetic treated with acarbose who suffers from pain and/or fever and asks for an analgesic?For patients who drink alcohol regularly, it would probably beprudent to avoid acetaminophen and to choose a nonsteroidal antiinflammatorydrug such as ibuprofen. For patients who do not drink alcoholand have no other risk factors for acetaminophen toxicity, I believethat the data currently available are not definitive enough towithhold therapeutic doses ofacetaminophen.

 Stephan Krähenbühl, M.D., Pharm.D.

        Institute of Clinical Pharmacology

                             University of Berne

                             Berne, Switzerland

Abbreviations

Abbreviations: CYP, cytochrome P450; NAPQI, N-acetyl-p-benzoquinoneimine.

Footnotes

Received October 28, 1998; accepted October 29, 1998.

From the Institute of Clinical Pharmacology, University of Berne, Berne,Switzerland.

Address reprint requests to: Stephan Krähenbühl, M.D., Pharm.D., Institute of Clinical Pharmacology, University of Berne, Murtenstrasse 35, CH-3010 Berne, Switzerland. E-mail: skraehen@ikp.unibe.ch; fax: (41) 31-632-49-97.

REFERENCES

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