title: Pharmacokinetics and tolerance of DU-6859a, a new fluoroquinolone, after single and multiple oral doses in healthy volunteers.
abstract: The pharmacokinetics and tolerance of DU-6859a, 7-[(7S)-7-amino-5-azaspiro[2,4]heptan-5-yl]-8-chloro-6-fluor o-1-[(1R, 2S)-2-fluoro-1-cyclopropyl]-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid sesquihydrate, were investigated in healthy male Japanese volunteers after single (25, 50, 100, and 200 mg) and multiple (100 mg three times a day for 6 days plus once a day on the 7th day and 50 mg every 12 h for 13 doses) oral doses. DU-6859a was well tolerated at all doses, and all 36 subjects completed the study; mild transient soft stool in five volunteers and mild transient diarrhea in one volunteer on the multiple-dose (100 mg three times a day) study were the only side effects reported. No drug crystals were observed in the urine after the single 200-mg dose and the 100-mg three times a day regimen. DU-6859a was rapidly absorbed in the fasted state. The mean maximum concentration in serum (Cmax) ranged from 0.29 to 1.86 micrograms/ml for the 25- to 200-mg dose, and the mean time to reach Cmax ranged from 1.0 to 1.3 h. The terminal half-life ranged from 4.4 to 5.0 h. The area under the curve increased dose dependently. The serum protein binding of the drug was approximately 50%. The apparent volume of distribution clearly exceeded 1 liter/kg, suggesting good tissue penetration. Within 48 h, the cumulative urinary recovery of unchanged drug amounted to 69 to 74% of the dose administered, while fecal excretion up to 48 h after the 200-mg dose accounted for ca. 3% of the dose. Food intake did not affect the rate and extend of absorption of DU-6859a to a clinically significant extent. During multiple oral dosing, the accumulation of the drug in serum was close to the theoretically predicted values, which indicated that there was virtually no drug accumulation.
authors.affiliation: Department of Pharmacology, Hamamatsu University School of Medicine, Shizuoka, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Nakashima
authors.forename: T
authors.initials: T
authors.lastname: Uematsu
authors.forename: K
authors.initials: K
authors.lastname: Kosuge
authors.forename: K
authors.initials: K
authors.lastname: Umemura
authors.forename: H
authors.initials: H
authors.lastname: Hakusui
authors.forename: M
authors.initials: M
authors.lastname: Tanaka
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000890:Anti-Infective Agents / Q000009:adverse effects / Q000493:pharmacokinetics*; D001798:Blood Proteins / Q000378:metabolism; D004334:Drug Administration Schedule; D004361:Drug Tolerance; D005215:Fasting / Q000378:metabolism; D024841:Fluoroquinolones; D006207:Half-Life; D006801:Humans; D007408:Intestinal Absorption; D008297:Male; D008875:Middle Aged; D015363:Quinolones / Q000009:adverse effects / Q000493:pharmacokinetics*; D013141:Spiro Compounds / Q000009:adverse effects / Q000493:pharmacokinetics*
chemical_list: D000890:Anti-Infective Agents; D001798:Blood Proteins; D024841:Fluoroquinolones; D015363:Quinolones; D013141:Spiro Compounds; C076246:sitafloxacin