title: Involvement of multiple transport systems in the disposition of an active metabolite of a prodrug-type new quinolone antibiotic, prulifloxacin.
abstract: Prulifloxacin is a prodrug-type new quinolone. The purpose of this study is to clarify the mechanism of biliary excretion and brain distribution of its active metabolite, UFX. UFX was efficiently excreted into the bile in rats, with its concentration in the bile being 30-60 times higher than that in plasma. The in vivo disposition study revealed that multidrug resistance-associated protein 2 (MRP2) was involved in the biliary excretion of glucuronide metabolite, but not of the unchanged UFX. A transport study using a P-glycoprotein (P-gp) overexpressing cell line, LLC-GA5-COL150, showed that UFX was a substrate of P-gp. Nevertheless, the biliary clearance (CLbile) of UFX in P-gp-gene-deficient mice was not different from that in the normal mice, although the concentration in the liver was slightly higher than that in the normal mice. These observations suggest that multiple transport systems are involved in the biliary excretion of UFX, with minor contribution of P-gp. The distribution of UFX in the rat brain was quite low, and its tissue to plasma concentration ratio (Kp) in the brain was much less than the unity and was increased by cyclosporin A. The Kp in the brain of mdr1a/1b(-/-) mice was higher than that in the normal mice, suggesting that efflux by P-gp played a major role in the limited brain distribution of UFX.
authors.affiliation: Toxicology & Pharmacokinetics Research Labs., Pharmaceutical Development Department, Meiji Seika Kaisha, LTD., Yokohama, Japan.
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Yagi
authors.forename: Sachiyo
authors.initials: S
authors.lastname: Shibutani
authors.forename: Naoko
authors.initials: N
authors.lastname: Hodoshima
authors.forename: Kazuya
authors.initials: K
authors.lastname: Ishiwata
authors.forename: Noriko
authors.initials: N
authors.lastname: Okudaira
authors.forename: Qing
authors.initials: Q
authors.lastname: Li
authors.forename: Yoshimichi
authors.initials: Y
authors.lastname: Sai
authors.forename: Yukio
authors.initials: Y
authors.lastname: Kato
authors.forename: Akira
authors.initials: A
authors.lastname: Tsuji