title: Multiple-dose pharmacokinetics of ofloxacin, a new broad-spectrum antimicrobial agent.
abstract: Twelve healthy male volunteers received 14 oral doses of ofloxacin (300 mg each), and the concentrations of the unchanged drug were measured at various times in serum and urine over a period of 15 days. Serum and urine ofloxacin concentrations were determined in specific assays using high-pressure liquid chromatography (HPLC); urine levels were also determined by means of a microbiological assay. A washout period of 72 hours followed the first and 14th doses, allowing comparison of serum pharmacokinetics at the beginning and end of the multiple-dose regimen. Doses 2 to 14 were administered at 12-hour intervals. Maximum serum concentration (Cmax), concentration at 12 hours after dosing (C12), and area under the serum concentration-time curve (0 to 72 hours) were all 1.3 to 1.7 times greater after the 14th dose than after the initial dose. A 1.6-fold increase in C12 was already evident after the third dose; C12 remained more or less constant thereafter. Thus it is concluded that ofloxacin rapidly attained steady-state serum levels under a multiple-dose regimen, at levels only slightly above those following a single dose. High serum Cmax levels (4.6 and 5.9 micrograms/ml after the first and 14th doses, respectively) and long serum half-lives (6.0 and 7.3 hours after the first and last doses, respectively) indicated long-lasting, clinically relevant serum ofloxacin concentrations after oral administration. Serum ofloxacin levels 24 hours after the last dose were in the range of 0.3 to 0.7 microgram/ml, above the minimal inhibitory concentration (MIC90) for most bacterial strains. Cumulative urinary recovery remained high throughout the study. After 14 doses of ofloxacin (total, 4.2 gm), 88% of the unchanged drug was recovered in the urine; urinary concentrations remained above 1 microgram/ml, far above the MIC90 for most bacterial strains, for at least 108 hours after the final dose. High renal clearance values relative to total clearance (98%) confirmed the importance of the renal elimination route. Determinations of ofloxacin in urine using a microbiological assay were in close agreement with the HPLC determinations for all samples obtained throughout the study. Thus no detectable appearance of active metabolites occurred under the multiple-dose regimen. Ofloxacin was well tolerated; mild, probably drug-induced side effects were reported by three subjects, but they did not require any countermeasures.
authors.forename: E E
authors.initials: EE
authors.lastname: Dagrosa
authors.forename: M
authors.initials: M
authors.lastname: Verho
authors.forename: V
authors.initials: V
authors.lastname: Malerczyk
authors.forename: S
authors.initials: S
authors.lastname: de Looze
authors.forename: P
authors.initials: P
authors.lastname: Hajdú
authors.forename: K
authors.initials: K
authors.lastname: Toyodera
mesh_terms: D000328:Adult; D000890:Anti-Infective Agents / Q000009:adverse effects / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D006801:Humans; D007700:Kinetics; D008297:Male; D008875:Middle Aged; D015242:Ofloxacin; D010078:Oxazines / Q000009:adverse effects / Q000378:metabolism*
chemical_list: D000890:Anti-Infective Agents; D010078:Oxazines; D015242:Ofloxacin