Disulfiram-like Reaction to Certain Cephalosporins

Uri, Joseph V.; Parks, Donald B.

doi:10.1097/00007691-198306000-00013

Cited by 41 publications

(24 citation statements)

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“…A disulfiram-like intolerance reaction has been reported with some cephalosporins after ingestion of alcohol (Allaz et al, 1979;Bailey et al, 1981 b;Foster et aI., 1980;McMahon, 1980;Neu and Prince, 1980;Portier et at, 1980;Reeves and Davies, 1980; see also review by Uri and Parks, 1983). The reaction is usually characterised by tachycardia, facial flushing, and dyspnoea.…”

Section: Alcohol Intolerancementioning

confidence: 97%

Clinical Pharmacokinetics of the Third Generation Cephalosporins

Balant

Dayer

Auckenthaler

1985

Clinical Pharmacokinetics

105

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At the present time, the third generation cephalosporins that are already on the market or close to this point include cefsulodin, cefotaxime, cefoperazone, latamoxef, ceftriaxone, ceftazidime, ceftizoxime and cefotetan. Other newer compounds are also under development but have not been included in this review. None of the third generation compounds is suitable for oral administration and, accordingly, their pharmacokinetics have been studied only after intravenous and intramuscular administration. Microbiological assays and HPLC methods have been used for the measurement of plasma/serum, urine, bile and cerebrospinal fluid (CSF) concentrations. As found with cefotaxime, microbiological assays should only be used when the full metabolite spectrum of a particular drug is known, as otherwise, the presence of microbiologically active metabolites may lead to erroneous conclusions. Under normal conditions, the major route of elimination is via the kidneys for cefsulodin, latamoxef, ceftazidime, ceftizoxime and cefotetan. In contrast, cefoperazone is mainly eliminated in the bile, whereas cefotaxime and ceftriaxone depend both on the liver and the kidneys for their elimination. With the exception of ceftriaxone, which has a longer elimination half-life (i.e. around 8 hours), all the other third generation cephalosporins have a t1/2 ranging between 1.5 and 2.5 hours. Plasma protein binding is variable from one compound to another. However, the clinical relevance of this parameter is not clearly established since tissue penetration also depends on the relative affinity of the drug for tissue components. Third generation cephalosporins seem to penetrate adequately into the CSF and, thus pharmacokinetically appear to be appropriate agents for the treatment of meningitis. The degree of modification of pharmacokinetic parameters by renal insufficiency or hepatic diseases depends, as for other drugs, on the extent to which the compound is excreted via the kidneys or the liver. The third generation cephalosporins have been extensively studied under these conditions and recommendations for dosage modification in special circumstances are available for most of them. The pharmacokinetics of some third generation cephalosporins may be modified in neonates and elderly patients. Accordingly, their use at the extremes of age must be accompanied by a closer than usual clinical monitoring of the patient. From a clinical point of view, the third generation cephalosporins possess reliable pharmacokinetic properties.(ABSTRACT TRUNCATED AT 400 WORDS)

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Section: Alcohol Intolerancementioning

confidence: 97%

Clinical Pharmacokinetics of the Third Generation Cephalosporins

Balant

Dayer

Auckenthaler

1985

Clinical Pharmacokinetics

105

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“…These com pounds specifically inhibit hepatic aldehyde dehydrogenase (EC 1.2.1.3, ALDH), which is an enzyme primarily involved in the metabolism of ethanol-derived acetal dehyde to acetic acid (2). Recently, several beta-lactam antibiotics, having an N methyltetrazolylthiomethyl group at the 3 position of the cephem nucleus, were re ported to display a reaction similar to that of disulfiram (3)(4)(5)(6). Subsequent studies showed that hepatic low Km ALDH activity was depressed markedly by the administration of ** To whom reprint requests should be addressed .…”

mentioning

confidence: 99%

Effects of alcohol-metabolizing enzyme inhibitors and beta-lactam antibiotics on ethanol elimination in rats.

et al. 1987

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Abstract-Thein vivo effects of alcohol-metabolizing enzyme inhibitors and beta lactam antibiotics upon the ethanol elimination rate were examined in rats. Intra venous administration of ethanol caused a dose-dependent increase in blood ethanol level, and the ethanol elimination could be well described by a two compart ment model.Pretreatment of rats with enzyme inhibitors caused a marked decrease in the ethanol elimination rate associated with the depression of the enzyme activities. Fasting of the animals caused a decrease in the ethanol elimination rate per animal associated with a decrease in the liver weight.However, no alteration was evident when the rate was expressed as the rate per g of liver. When animals were pre treated with a high dose of N-methyltetrazolethiol (NMTT) containing beta-lactam antibiotics or NMTT itself, which causes a disulfiram-like reaction, the ethanol elimination rate per animal was depressed concomitant with an increase in the blood acetaldehyde level. The ethanol elimination rate in these animals showed lower values even when expressed as the rate per g liver. On the other hand, administration of cephems without NMTT, which cause no disulfiram-like reaction, led to a slight decline in the elimination rate per animal, although no alteration was detected when the rate was expressed as the rate per g liver. The findings indicated that the ethanol elimination in vivo per animal is regulated by the total capacity of the alcohol-metabolizing enzyme activities in the whole liver.

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“…NMTT is a common 3'-position substi tuent of the cephalosporin nucleus of beta lactam antibiotics, which display a disul firam-like reaction (2)(3)(4)(5)(6)(7)(8)(9)(10)21). Adminis tration of NMTT resulted in a rapid onset of the disulfiram-like reaction in rats (Figs.…”

Section: Methodsmentioning

confidence: 99%

Effects of beta-lactam antibiotics and N-methyltetrazolethiol on the alcohol-metabolizing system in rats.

et al. 1987

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Abstract-The disulfiram-like effect of various beta-lactam antibiotics containing N-methyltetrazolethiol (NMTT) on the alcohol-metabolizing system was studied using rats. Their administration caused decreased activities in low Km aldehyde dehydrogenase (ALDH) and acetaldehyde oxidation in the liver, with marked depression from several hours to 2 days after the treatment.Blood acetaldehyde level increased markedly when ethanol was administered 18-24 hr after pretreat ment with antibiotics.A similar time course change in the effect was obtained when disulfiram was administered.The following results obtained in the present study indicate that the disulfiram-like effect associated with these antibiotics was not mediated by the whole molecular structures of these drugs: Firstly, the antibiotics were eliminated rapidly from the plasma and liver, and the disulfiram like effect was followed by a disappearance of the drugs. Secondly, the concen tration of antibiotics required to inhibit mitochondrial low Km ALDH activity in vitro was very high compared with their liver concentration.Thirdly, rapid onset of disulfiram-like effects occurred after administration of NMTT itself, and a pronounced elevation of blood acetaldehyde level was observed when ethanol was administered 3-5 hr after the NMTT injection. Fourthly, almost the same amounts of NMTT were released in the body after the intravenous administration of various NMTT-containing antibiotics, as judged by the urinary excretion. These results suggest that the disulfiram-like effect of beta-lactam antibiotics is mediated by NMTT released from them.

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Disulfiram-like Reaction to Certain Cephalosporins

Cited by 41 publications

References 0 publications

Clinical Pharmacokinetics of the Third Generation Cephalosporins

Clinical Pharmacokinetics of the Third Generation Cephalosporins

Effects of alcohol-metabolizing enzyme inhibitors and beta-lactam antibiotics on ethanol elimination in rats.

Effects of beta-lactam antibiotics and N-methyltetrazolethiol on the alcohol-metabolizing system in rats.

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