Depression of liver microsomal vitamin K epoxide reductase activity associated with antibiotic-induced coagulopathy

Matsubara, Takashi; Touchi, Akira; Harauchi, Toshio; Takano, Kyoji; Yoshizaki, Toshio

doi:10.1016/0006-2952(89)90556-x

Cited by 21 publications

(15 citation statements)

References 34 publications

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“…Antibiotics known to cause clotting factor deficiencies include cefoperazone and those with N-methylthiotetrazol(NMTT) side chains [2,3]. These have been reported to reduce the levels of reduced forms of vitamin K and prolong PT by inhibiting vitamin K epoxide reductase [4].…”

Section: Discussionmentioning

confidence: 99%

Coagulopathy Induced by Cefoperazone/Sulbactam in a Geriatric Patient

Karagöz¹,

Özalper²,

Ülçay³

et al. 2015

Med-Science

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Section: Discussionmentioning

confidence: 99%

Coagulopathy Induced by Cefoperazone/Sulbactam in a Geriatric Patient

Karagöz¹,

Özalper²,

Ülçay³

et al. 2015

Med-Science

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“…Moxalactam has not been found to affect the levels of vitamin K-dependent clotting factors II, VII, IX, and X or vitamin K-independent clotting factors V, VIII, and I. Moxalactarn, and 27 out of the 33 additional beta-Iactarn antibiotics investigated, were found to suppress ADP-induced platelet aggregation at high concentrations in vitro. Many newer therapeutic agents and older broad-spectrum antibiotics induce hypoprothrombinemia with or without bleeding complications in weaker patients due to the suppression of intestinal bacteria that synthesize vitamin K (40)(41)(42) and in the lowering of liver microsomal vitamin K epoxide reductase activity and thus causing hypoprothrombinemia even in the presence of vitamin K sufficiency. Moreover vitamin K administration could normalize the blood coagulation parameters in hypoprothrombinemic rats caused by antibiotic treatment, but without recovery of the reduced epoxide reductase activity (41,42).…”

Section: Discussionmentioning

confidence: 99%

Anticoagulant-induced changes on antibiotic concentrations in the serum and bones

Kotsiou

Diamanti

Potamianou

et al. 2008

Eur. J. Drug Metabol. Pharmacokinet.

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The aim of this study was to determine whether the co-administration of acenocoumarin as anticoagulant and certain quinolones, i.e., cefapirin, pefloxacin and ciprofloxacin increased the levels of the given antibiotics and whether this resulted in a prolongation of prothrombin time. Seventy male albino Wistar rats aged 8-10 weeks and weighed 170 +/- 14 g were used and divided into seven groups (I, II, III, IV, V, VI, VII: n=10). The rats in group I received cefapirin via 1 g/kg/8h im injection. Group II received cefapirin via of 1 g/kg/8h im injection and 0.1 mg/kg/24h p.o. acenocoumarin. Group III received ciprofloxacin 0.18 mg/kg/24h im. Group IV received ciprofloxacin 0.18 mg/kg/24h im and 0.1 mg/kg/24h p.o. acenocoumarin. Group V received 10 mg/kg/24h pefloxacin im. Group VI received 10 mg/kg/24h pefloxacin im and 0.1 mg/kg/24h p.o. acenocoumarin while Group VII received only acenocoumarin 0.1 mg/kg/24h p.o. Drug administration was performed over a total of 5 doses in order to obtain steady state concentrations in the plasma and tissues. The animals were sacrificed by decapitation 2 h after the last antibiotic administration. Prothrombin time and antibiotic concentrations in the serum, femur and mandible were assessed. In the study, all the antibiotics were found to prolong prothrombine time following acenocoumarin administration. In addition, perfloxacin and ciproflaxin concentrations were increased in the serum and mandible after acenocoumarin treatment. Cepafirin levels remained unaffected after the administration of this anticoagulant. In conclusion, anticoagulant and quinolone co-administration led to significant pharmacokinetic interactions. Thus particular attention should be paid in the case of these drugs being used in combination in clinical practice.

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“…[87][88][89] We clariˆed that NMTT released from antibiotics inhibits vitamin K epoxide reductase activity in liver microsomes, which causes the development of hypoprothrombinemia under vitamin K deˆcient conditions. [90][91][92] Fortunately, inhibitory action of HTT on vitamin K epoxide reductase was weaker than that of NMTT. [90][91][92] These results indicated also that several risk caused by NMTT was able to avoid by substitution from NMTT to HTT as the 3?-position substituent of cephem antibiotics.…”

Section: Species Dišerence In the Susceptibility Of Cytochrome P450mentioning

confidence: 99%

“…[90][91][92] Fortunately, inhibitory action of HTT on vitamin K epoxide reductase was weaker than that of NMTT. [90][91][92] These results indicated also that several risk caused by NMTT was able to avoid by substitution from NMTT to HTT as the 3?-position substituent of cephem antibiotics.…”

Section: Species Dišerence In the Susceptibility Of Cytochrome P450mentioning

confidence: 99%

Safety Evaluation and Drug Development based on Biological Fate of Drugs —Efforts Made to Overcome Drug Interaction in Drug Development—

Matsubara¹

2002

Drug Metabolism and Pharmacokinetics

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1. Assay methods to detect drug interaction in toxicological samples were established by determining cytochrome P450 content and its activity in liver samples. The O-dealkylation reaction of 7-alkoxycoumarin was indicated to reflect changes in the molecular forms of P450s, and the enzyme induction or inhibition in the toxicological samples was easily detected by using the established methods. 2. During toxicological studies of 450191-S or the sleep inducer rilmazafone, a phenobarbital type-induction of hepatic drug metabolizing enzymes was observed in animals, and the doses required for the induction differed markedly between rats and dogs. Enzyme induction was caused by some specific metabolites of 450191-S, and the plasma concentrations of these metabolites were comparable when the enzyme induction was developed in both animals. 3. A nonsteroidal antiinflammatory compound 480156-S showed a slight or no effect on microsomal drug metabolizing activity in rats. On the other hand, repeated administration of this compound to humans resulted in a marked decrease in the oxidative metabolism of 480156-S, followed by a marked increase in the plasma concentrations of the compound. When volunteers were given 480156-S followed by several drugs, such as tolubutamide, the plasma clearance was delayed remarkably, indicating a severe drug interaction. 4. Cytochrome P450 belonging to the CYP2C family was indicated to participate in the oxidative metabolism of 480156-S in both rat and human liver microsomes. The preincubation of microsomes with 480156-S caused a concentration-dependent inhibition of CYP2C-dependent tolubutamide hydroxylation reaction in both rats and humans. There was a marked species difference in the susceptibility to the inhibitory effect of 480156-S, and the concentration required to inhibit rat CYP2C was almost 10 times higher than that required in humans. 5. The cephem antibiotics having N-methyltetrazolethiol (NMTT) at the 3'-position substituent were demonstrated to inhibit mitochondrial low K(m) aldehyde dehydrogenase (ALDH), and produced disulfiram-like (Antabuse) reaction during alcohol metabolism. Pharmacokinetic studies indicated that NMTT released from the antibiotics in bile duct or intestine cause the inhibitory action followed by the development of disulfiram-like reaction. 6. Attempts had been made to develop new cephem antibiotics lacking the disulfiram-like reaction by changing the chemical structure of 3'-position substituents, and a hydroxyethyltetrazolethiol was found not to inhibit the enzyme. Based on this result, together with the antibacterial activity, we have developed a new oxacephem antibiotic flomoxef (6315-S). Flomoxef showed no disulfiram-like reaction both in rats and human.

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Depression of liver microsomal vitamin K epoxide reductase activity associated with antibiotic-induced coagulopathy

Cited by 21 publications

References 34 publications

Coagulopathy Induced by Cefoperazone/Sulbactam in a Geriatric Patient

Coagulopathy Induced by Cefoperazone/Sulbactam in a Geriatric Patient

Anticoagulant-induced changes on antibiotic concentrations in the serum and bones

Safety Evaluation and Drug Development based on Biological Fate of Drugs —Efforts Made to Overcome Drug Interaction in Drug Development—

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