title: Investigation of the safety of topical metronidazole from a pharmacokinetic perspective.
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.
authors.affiliation: Research Institute of Pharmaceutical Sciences, Musashino University, 1–1–20 Shinmachi, Nishitokyo, Tokyo 202–8585, Japan.
authors.forename: Junichi
authors.initials: J
authors.lastname: Iida
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Kudo
authors.forename: Kento
authors.initials: K
authors.lastname: Shimada
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Yatsuno
authors.forename: Saori
authors.initials: S
authors.lastname: Yamagishi
authors.forename: Satoshi
authors.initials: S
authors.lastname: Hasegawa
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Ike
authors.forename: Toru
authors.initials: T
authors.lastname: Sato
authors.forename: Hajime
authors.initials: H
authors.lastname: Kagaya
authors.forename: Kiyomi
authors.initials: K
authors.lastname: Ito
mesh_terms: D000287:Administration, Topical; D000818:Animals; D000890:Anti-Infective Agents / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D000925:Anticoagulants / Q000378:metabolism; D001943:Breast Neoplasms / Q000150:complications / Q000188:drug therapy*; D018270:Carcinoma, Ductal, Breast / Q000150:complications / Q000188:drug therapy*; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D004347:Drug Interactions; D005260:Female; D006801:Humans; D008099:Liver / Q000378:metabolism; D008297:Male; D008795:Metronidazole / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D008862:Microsomes, Liver / Q000378:metabolism; D008875:Middle Aged; D009812:Odorants; D009824:Ointments; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014859:Warfarin / Q000378:metabolism
chemical_list: D000890:Anti-Infective Agents; D000925:Anticoagulants; D009824:Ointments; D012333:RNA, Messenger; D008795:Metronidazole; D014859:Warfarin; D003577:Cytochrome P-450 Enzyme System