Investigation of the Safety of Topical Metronidazole from a Pharmacokinetic Perspective

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...

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Veröffentlicht in:Biological & pharmaceutical bulletin 2013/01/01, Vol.36(1), pp.89-95
Hauptverfasser: Iida, Junichi, Kudo, Toshiyuki, Shimada, Kento, Yatsuno, Yoshiyuki, Yamagishi, Saori, Hasegawa, Satoshi, Ike, Hideyuki, Sato, Toru, Kagaya, Hajime, Ito, Kiyomi
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container_title Biological & pharmaceutical bulletin
container_volume 36
creator Iida, Junichi
Kudo, Toshiyuki
Shimada, Kento
Yatsuno, Yoshiyuki
Yamagishi, Saori
Hasegawa, Satoshi
Ike, Hideyuki
Sato, Toru
Kagaya, Hajime
Ito, Kiyomi
description 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.
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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. 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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. 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pharmaceutical bulletin</jtitle><addtitle>Biol Pharm Bull</addtitle><date>2013-01-01</date><risdate>2013</risdate><volume>36</volume><issue>1</issue><spage>89</spage><epage>95</epage><pages>89-95</pages><issn>0918-6158</issn><eissn>1347-5215</eissn><abstract>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.</abstract><cop>Japan</cop><pub>The Pharmaceutical Society of Japan</pub><pmid>23302640</pmid><doi>10.1248/bpb.b12-00687</doi><tpages>7</tpages><oa>free_for_read</oa></addata></record>
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subjects Administration, Topical
Animals
Anti-Infective Agents - administration & dosage
Anti-Infective Agents - blood
Anti-Infective Agents - pharmacokinetics
Anticoagulants - metabolism
Breast Neoplasms - complications
Breast Neoplasms - drug therapy
cancerous malodor
Carcinoma, Ductal, Breast - complications
Carcinoma, Ductal, Breast - drug therapy
Cytochrome P-450 Enzyme System - genetics
cytochrome P450
drug interaction
Drug Interactions
Female
Humans
Liver - metabolism
Male
metronidazole
Metronidazole - administration & dosage
Metronidazole - blood
Metronidazole - pharmacokinetics
Microsomes, Liver - metabolism
Middle Aged
Odorants
Ointments
Rats
Rats, Sprague-Dawley
RNA, Messenger - metabolism
Warfarin - metabolism
title Investigation of the Safety of Topical Metronidazole from a Pharmacokinetic Perspective
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