Cefazolin administration and 2-methyl-1,3,4-thiadiazole-5-thiol (MTD) in human tissue

T. C. Wood, K. L. Johnson, S. Naylor, Richard M Weinshilboum

Research output: Contribution to journalArticle

Abstract

Cephalosporin antibiotic administration can lead to the formation of heterocyclic thiol metabolites that have been associated with hypoprothrombinemia and hemorrhage. The cefazolin structure includes a heterocyclic thiol, MTD, that can inhibit the γ-carboxylation of glutamate required to produce active clotting factors. We set out to determine whether MTD might be present in tissue from patients treated with cefazolin prior to clinically-indicated surgery. To test that hypothesis, we took advantage of the fact that heterocyclic thiols can be S-methylated by thiopurine methyltransferase (TPMT). As a first step, recombinant human TPMT was used to S-methylate MTD. MTD was a TPMT substrate with an apparent K m of 63 μM. TPMT was then used to radioactively label a methyl acceptor substrate present in liver and kidney cytosol from patients treated preoperatively with cefazolin. Pooled renal cytosol was then used to isolate the methylated product by reverse-phase HPLC. The methylated product in kidney cytosol coeluted with methylated MTD during HPLC. When this methylated product was subjected to tandem mass spectroscopy, it was identified as S-methyl-MTD. MTD, an inhibitor of clotting factor activation, is present in the tissues of patients treated with cefazolin.

Original languageEnglish (US)
JournalClinical Pharmacology and Therapeutics
Volume69
Issue number2
StatePublished - 2001

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thiopurine methyltransferase
Cefazolin
Sulfhydryl Compounds
Cytosol
Blood Coagulation Factors
Kidney
Hypoprothrombinemias
High Pressure Liquid Chromatography
Cephalosporins
Glutamic Acid
Mass Spectrometry
Hemorrhage
2-methyl-1,3,4-thiadiazole-5-thiol
Liver

ASJC Scopus subject areas

  • Pharmacology

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Cefazolin administration and 2-methyl-1,3,4-thiadiazole-5-thiol (MTD) in human tissue. / Wood, T. C.; Johnson, K. L.; Naylor, S.; Weinshilboum, Richard M.

In: Clinical Pharmacology and Therapeutics, Vol. 69, No. 2, 2001.

Research output: Contribution to journalArticle

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AU - Weinshilboum, Richard M

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