Hydroxywarfarin Metabolites Potently Inhibit CYP2C9 Metabolism of <i>S</i>-Warfarin

Jones, Drew R.; Kim, Soyoung; Guderyon, Michael; Yun, Chul‐Ho; Moran, Jeffery H.; Miller, Grover P.

doi:10.1021/tx1000283

Cited by 37 publications

(34 citation statements)

References 29 publications

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“…The CL int values for S-WAR 6-hydroxylation and 7-hydroxylation obtained in the present HLM study were within the range of reported values (0.014-12 µL/min/mg protein and 0.26-33 µL/min/mg protein, respectively 20,45) ) which were also estimated by in vitro studies using HLM. In an S-WAR metabolic inhibition study using HLM, S-WAR metabolism was only inhibited about 30% when MTZ was added at a high concentration (6000 µm).…”

Section: Discussionsupporting

confidence: 88%

Section: )mentioning

confidence: 99%

“…CYP2C8, CYP2C18 and CYP2C19 are also involved in the metabolism of R-WAR. [17][18][19][20] Therefore, it is possible that the above interaction was caused by inhibition of CYP2C9-mediated 7-and 6-hydroxylation of S-WAR by MTZ.Although MTZ has long been used in clinical practice, few studies have investigated the drug interactions involving MTZ, with some controversial findings. [21][22][23][24] In the present study, both clinical and basic researches were conducted with the objective of investigating the safety of topical MTZ preparation from a pharmacokinetic perspective.…”

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confidence: 99%

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Investigation of the Safety of Topical Metronidazole from a Pharmacokinetic Perspective

Iida

Kudo

Shimada

et al. 2013

Biological & Pharmaceutical Bulletin

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Metronidazole (MTZ) ointment has been used widely as a hospital preparation against cancerous malodor. Although cancerous tissue with ulcer-like symptoms is likely to have a higher capacity to absorb drugs than normal skin, the extent to which MTZ is absorbed when a topical preparation is applied to cancerous tissue remains unclear. Furthermore, few studies have investigated the drug interactions involving MTZ despite its long use in clinical practice. In the present study, plasma concentration of MTZ was measured in a breast cancer patient using MTZ ointment for cancerous malodor and basic research was also conducted with the objective of investigating the safety of topical MTZ from a pharmacokinetic perspective. 4.75 µg/mL (27.8 µm) of MTZ was detected in the patient's plasma, which was close to the plasma concentration after oral dosage of MTZ. In a metabolic inhibition study using human liver microsomes, cytochrome P450 (CYP) 2C9-mediated hydroxylation of S-warfarin was almost unaffected by MTZ at the corresponding concentrations. In addition, 3-d repeated oral administration of MTZ (200 mg/kg/d) to rats did not show any significant effects on the hepatic mRNA levels of various CYP isozymes and CYP2C protein levels. These results suggest that the reported interaction of oral MTZ and S-warfarin was not due to CYP2C9 inhibition and that drug interactions via inhibition of CYP2C9 is unlikely to occur when MTZ ointment is applied to ulcerous skin. This information should be valuable for assessing the safety of MTZ ointment used for mitigating cancerous malodor.Key words metronidazole; cytochrome P450; drug interaction; cancerous malodor Invasion and metastasis of malignant tumors to the skin (continuous, hematogenous, lymphogenous metastasis to the skin), complicated by the infection of ulcerated skin cancer tissue, results in the emission of an intense malodor.1-3) Malodor causes discomfort to the patient, of course, but also to people in the vicinity of the patient, such as family members and healthcare workers, and can make it difficult to maintain human relationships, damage the self-esteem of the patient, and cause a decrease in quality of life. Volatile sulfides and volatile fatty acids produced by anaerobic bacteria (such as Bacteroides fragilis) that have infected sites of ulceration are suggested to contribute to malodor.2-5) The application of topical metronidazole (MTZ) preparations has been reported to be effective against cancerous malodor, 2,3,6) but because topical MTZ preparations are not sold in Japan, many hospitals prepare these agents in-house. A survey of the literature conducted by the Japanese Society of Hospital Pharmacists 7) in 2010 reported that topical MTZ preparations were prepared at standards between 0.75% and 1%, with an average one-time dose of 70 g. The plasma MTZ concentration of 32 ng/mL has been reported when 1 g of 1% MTZ gel was applied to the face once daily for 7 d. 8) Cancerous tissue with ulcer-like symptoms is likely to have a higher capacity to absorb drugs than norma...

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Section: Discussionsupporting

confidence: 88%

Section: )mentioning

confidence: 99%

mentioning

confidence: 99%

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Investigation of the Safety of Topical Metronidazole from a Pharmacokinetic Perspective

Iida

Kudo

Shimada

et al. 2013

Biological & Pharmaceutical Bulletin

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“…1 If any of these warfarin metabolites are potent vitamin K antagonists, drug-drug or drug-gene interactions involving the enzymes that generate them, or metabolize them further (eg, by glucuronidation), could affect a patient's response to warfarin. 33 Beyond the possible implications for warfarin patient response these structure-function studies may also provide insight into the molecular interactions between warfarin and VKOR that are required for enzyme inhibition.…”

Section: Discussionmentioning

confidence: 99%

A cellular system for quantitation of vitamin K cycle activity: structure-activity effects on vitamin K antagonism by warfarin metabolites

Haque

McDonald

Kulman

et al. 2014

Blood

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• Factor IX glutamyl carboxylation in engineered HEK 293 cells recapitulates in vivo anticoagulant inhibition of vitamin K cycle activity.• Warfarin metabolite structureactivity analysis on vitamin K cycle antagonism determines their contributions to in vivo anticoagulation.Warfarin and other 4-hydroxycoumarins inhibit vitamin K epoxide reductase (VKOR) by depleting reduced vitamin K that is required for posttranslational modification of vitamin K-dependent clotting factors. In vitro prediction of the in vivo potency of vitamin K antagonists is complicated by the complex multicomponent nature of the vitamin K cycle. Here we describe a sensitive assay that enables quantitative analysis of g-glutamyl carboxylation and its antagonism in live cells. We engineered a human embryonic kidney (HEK) 293-derived cell line (HEK 293-C3) to express a chimeric protein (F9CH) comprising the Gla domain of factor IX fused to the transmembrane and cytoplasmic regions of proline-rich Gla protein 2. Maximal g-glutamyl carboxylation of F9CH required vitamin K supplementation, and was dose-dependently inhibited by racemic warfarin at a physiologically relevant concentration. Cellular g-glutamyl carboxylation also exhibited differential VKOR inhibition by warfarin enantiomers (S > R ) consistent with their in vivo potencies. We further analyzed the structure-activity relationship for inhibition of g-glutamyl carboxylation by warfarin metabolites, observing tolerance to phenolic substitution at the C-5 and especially C-6, but not C-7 or C-8, positions on the 4-hydroxycoumarin nucleus. After correction for in vivo concentration and protein binding, 10-hydroxywarfarin and warfarin alcohols were predicted to be the most potent inhibitory metabolites in vivo. (Blood. 2014;123(4):582-589)

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“…(S)-warfarin is metabolized almost exclusively by CYP2C9. 5,6,7 Warfarin metabolism. (Warfarin is metabolized inside the liver.…”

Section: Metabolismmentioning

confidence: 99%

Acute Warfarin Toxicity due to Interaction between Warfarin and Amiodarone

Fera¹

2017

JMSCR

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Hydroxywarfarin Metabolites Potently Inhibit CYP2C9 Metabolism of S-Warfarin

Cited by 37 publications

References 29 publications

Investigation of the Safety of Topical Metronidazole from a Pharmacokinetic Perspective

Investigation of the Safety of Topical Metronidazole from a Pharmacokinetic Perspective

A cellular system for quantitation of vitamin K cycle activity: structure-activity effects on vitamin K antagonism by warfarin metabolites

Acute Warfarin Toxicity due to Interaction between Warfarin and Amiodarone

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