title: Endotoxin impairs biliary transport of sparfloxacin and its glucuronide in rats.
abstract: The effect of endotoxin on glucuronidation and hepatobiliary transport of quinolone antimicrobial agents was investigated in rats using sparfloxacin and p-nitrophenyl glucuronide as model drugs. The biliary clearance experiments were performed 24 h after a single intraperitoneal injection of endotoxin (1 mg/kg). Endotoxin significantly delayed the disappearance of sparfloxacin from plasma and increased plasma concentration of its glucuronide after intravenous injection of sparfloxacin (10 mg/kg). Significant decreases in the systemic clearance of sparfloxacin and the biliary clearance of sparfloxacin and the glucuronide were observed. Endotoxin had no effect on in vitro glucuronidation activity using p-nitrophenol as a substrate. When p-nitrophenyl glucuronide (8 mg/kg) was administered in endotoxin-pretreated rats, significant decreases in the systemic clearance, biliary clearance and renal clearance of p-nitrophenyl glucuronide were observed. These findings suggest that endotoxin decreases the biliary excretion of sparfloxacin and its glucuronide probably due to impairment of their hepatobiliary transport systems and renal handling.
authors.affiliation: Faculty of Pharmacy, Meijo University, 150 Yagotoyama, Tenpaku-ku, 468-8503, Nagoya, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Nadai
authors.forename: Y L
authors.initials: YL
authors.lastname: Zhao
authors.forename: L
authors.initials: L
authors.lastname: Wang
authors.forename: Y
authors.initials: Y
authors.lastname: Nishio
authors.forename: K
authors.initials: K
authors.lastname: Takagi
authors.forename: K
authors.initials: K
authors.lastname: Kitaichi
authors.forename: K
authors.initials: K
authors.lastname: Takagi
authors.forename: H
authors.initials: H
authors.lastname: Yoshizumi
authors.forename: T
authors.initials: T
authors.lastname: Hasegawa
mesh_terms: D000818:Animals; D000890:Anti-Infective Agents / Q000493:pharmacokinetics*; D001652:Bile Ducts / Q000187:drug effects* / Q000378:metabolism; D001692:Biological Transport / Q000187:drug effects; D004731:Endotoxins / Q000494:pharmacology*; D024841:Fluoroquinolones; D020719:Glucuronides / Q000378:metabolism / Q000493:pharmacokinetics*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008657:Metabolic Clearance Rate; D009596:Nitrophenols / Q000378:metabolism / Q000652:urine; D051381:Rats; D017208:Rats, Wistar; D013379:Substrate Specificity; D013997:Time Factors
chemical_list: D000890:Anti-Infective Agents; D004731:Endotoxins; D024841:Fluoroquinolones; D020719:Glucuronides; D009596:Nitrophenols; C061363:sparfloxacin; C024836:4-nitrophenol