Antibiotics Alter Methotrexate Metabolism and Excretion

Zaharko, Daniel S.; Bruckner, Howard W.; Oliverio, Vincent T.

doi:10.1126/science.166.3907.887

Cited by 80 publications

(15 citation statements)

References 7 publications

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“…When DAMPA, a nontoxic metabolite of MTX produced by the bacterial enzyme CPDG2, 13 , 14 was quantified in fecal samples, its excretion positively correlated with the relative abundances of the Prevotellaceae and Anaeroplasmataceae . These bacterial families were themselves positively correlated with glutamate, which suggests that they are able to produce the CPDG2 enzyme.…”

Section: Discussionmentioning

confidence: 99%

A Two-Way Interaction between Methotrexate and the Gut Microbiota of Male Sprague–Dawley Rats

et al. 2020

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Methotrexate (MTX) is a chemotherapeutic agent that can cause a range of toxic side effects including gastrointestinal damage, hepatotoxicity, myelosuppression, and nephrotoxicity and has potentially complex interactions with the gut microbiome. Following untargeted UPLC-qtof-MS analysis of urine and fecal samples from male Sprague–Dawley rats administered at either 0, 10, 40, or 100 mg/kg of MTX, dose-dependent changes in the endogenous metabolite profiles were detected. Semiquantitative targeted UPLC-MS detected MTX excreted in urine as well as MTX and two metabolites, 2,4-diamino- N -10-methylpteroic acid (DAMPA) and 7-hydroxy-MTX, in the feces. DAMPA is produced by the bacterial enzyme carboxypeptidase glutamate 2 (CPDG2) in the gut. Microbiota profiling (16S rRNA gene amplicon sequencing) of fecal samples showed an increase in the relative abundance of Firmicutes over the Bacteroidetes at low doses of MTX but the reverse at high doses. Firmicutes relative abundance was positively correlated with DAMPA excretion in feces at 48 h, which were both lower at 100 mg/kg compared to that seen at 40 mg/kg. Overall, chronic exposure to MTX appears to induce community and functionality changes in the intestinal microbiota, inducing downstream perturbations in CPDG2 activity, and thus may delay MTX detoxication to DAMPA. This reduction in metabolic clearance might be associated with increased gastrointestinal toxicity.

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Section: Discussionmentioning

confidence: 99%

A Two-Way Interaction between Methotrexate and the Gut Microbiota of Male Sprague–Dawley Rats

et al. 2020

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“…These reactions may be catalyzed by hydrolases classified into EC 3.5 and EC 3.10 groups, which are commonly found in probiotic bacteria. One of the first observations of drug biotransformation via hydrolysis was methotrexate metabolism by the intestinal flora of normal mice (Zaharko et al, 1969). Hydrolytic enzymes produced by the gut microflora play a significant role in the activation of some orally administered prodrugs in the form of phosphate or sulphate esters which are used to improve poor biopharmaceutical properties of drugs, particularly solubility (Wilson and Nicholson, 2017).…”

Section: Discussionmentioning

confidence: 99%

Transport and Biotransformation of Gliclazide and the Effect of Deoxycholic Acid in a Probiotic Bacteria Model

et al. 2019

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Introduction: Inter-individual differences in gut microflora composition may affect drug metabolism and overall therapeutic response. Gliclazide is a drug characterized by large inter-individual differences in therapeutic response; however, the causes of these differences are not fully explained and may be the outcome of microbial biotransformation. Recently, great attention has been paid to studies on bile acid (BA) interactions with gut microflora and the role of BAs in the modification of drug transport through biological membranes.The Aim: Considering the assumption of gliclazide–probiotic–BAs interactions, the aim of the study was to investigate the transport and biotransformation of gliclazide in probiotic bacteria, as well as the effects of deoxycholic acid (DCA) on gliclazide transport into bacterial cells.Materials and Methods: Probiotics were incubated with gliclazide with or without DCA for 24 h at 37°C. The intracellular and extracellular concentrations of gliclazide were determined at seven time points by high-performance liquid chromatography. Gliclazide biotransformation by the enzymatic activity of probiotic bacteria was examined using appropriate software packages.Results: During the 24 h incubation with probiotic bacteria, significantly lower extracellular concentrations of gliclazide were observed at all time points compared to controls, while in the group with DCA, the decrease in concentration was noticed only at 24 h. The total concentration of gliclazide throughout the whole period was significantly lower compared to control. Proposed pathways of gliclazide biotransformation by probiotic bacteria involve reactions of hydrolysis and hydroxylation.Conclusion: Based on the results obtained, it can be concluded that there are interactions of gliclazide–probiotics–DCA, at both the level of active and passive transport into the cells, and at the level of drug biotransformation by enzymatic activity of probiotic bacteria. The effect of these interactions on the final therapeutic response of gliclazide should be further studied and confirmed in in vivo conditions.

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“…1 ' Inhibition of gastrOintestinal tract bacteria with neomycin in mice prevented the formation of these metabolites. 31 Mtx can serve as a substrate for a Pseudomonas carboxypeptidase enzyme. 3 ,19 In one experiment we found that the incubation of feces with 3H-Mtx resulted in a radioactive peak that was chromatographically distinct from the urinary metabolite we observed in vivo.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics of methotrexate

Huffman

Wan

Azarnoff

et al. 1973

Clin Pharma and Therapeutics

129

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The pharmacokinetics of SH‐methotrexate were studied in 22 patients with malignancies. Following the intravenous administration of 30 mg methotrexate (Mtx) per square meter, the plasma disappearance was triphasic with half‐lifes of 0.7.5 ± 0.11,3.49 ± 0 . .55, and 26.99 ± 4.44 hours, respectively. The urinary excretion of radioactivity paralleled the plasma data for most patients. A metabolite was found in urine that eluted before Mix when chromatographed on a diethylaminoethyl (DEAE) cellulose column. The excretion of this metabolite reached steady state and accounted for 20 (14 to 37) per cent of the radioactivity in urine after 30 hours. Our observation that Mtx has a long terminal half‐life may explain the high incidence of tOXicity in patients receiving chronic low‐dose Mtx therapy.

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Antibiotics Alter Methotrexate Metabolism and Excretion

Cited by 80 publications

References 7 publications

A Two-Way Interaction between Methotrexate and the Gut Microbiota of Male Sprague–Dawley Rats

A Two-Way Interaction between Methotrexate and the Gut Microbiota of Male Sprague–Dawley Rats

Transport and Biotransformation of Gliclazide and the Effect of Deoxycholic Acid in a Probiotic Bacteria Model

Pharmacokinetics of methotrexate

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