Single- and multiple-dose pharmacokinetics of AM-1155, a new 6-fluoro-8-methoxy quinolone, in humans.
The pharmacokinetics of AM-1155, a new 6-fluoro-8-methoxy quinolone, was examined in healthy male volunteers after the oral administration of a single dose of 100, 200, 400, or 600 mg and multiple doses of 300 mg twice daily for 6.5 days (13 total doses). Throughout the whole study period, AM-1155 was well tolerated in every subject. In the single-dose study, the concentrations in serum reached a peak between 1 and 2 h, and the peak concentrations were 0.873, 1.71, 3.35, and 5.41 micrograms/ml at the doses of 100, 200, 400, and 600 mg, respectively. The elimination half-life was 7 to 8 h, independently of the doses. The unchanged drug was excreted mainly in the urine, with 82 to 88% of the doses appearing for 72 h. The fecal recovery of the unchanged drug amounted to 5.7% for 72 h after a single oral administration of a 400-mg dose. Urinary excretion of metabolites was minimal. The serum protein binding was 20%, independently of the concentrations in serum. The concentrations in saliva were approximately 80% of those in serum. The intake of food had no effect on the pharmacokinetic parameters and urinary excretion of AM-1155 except the slight decrease in area under the concentration-time curve. The concurrent administration of probenecid prolonged the elimination half-life, increased the area under the concentration-time curve, and decreased the apparent total body clearance, renal clearance, urinary recovery of unchanged drug, and the excretion ratio (intrinsic renal clearance of AM-1155/creatinine clearance). This indicated that the tubular secretion contributed to the renal excretion of AM-1155. In the multiple-dose study, the concentrations of AM-1155 in serum and urine reached a steady state within 2 to 3 days. The measured concentrations in serum fitted well the simulation curve, which reflected the persistence of linear pharmacokinetics of AM-1155. In conclusion, AM-1155 is expected to be clinically useful because of its potent antibacterial activity and favorable pharmacokinetics.
Nakashima
M
M
Department of Pharmacology, Hamamatsu University School of Medicine, Japan.
Uematsu
T
T
Kosuge
K
K
Kusajima
H
H
Ooie
T
T
Masuda
Y
Y
Ishida
R
R
Uchida
H
H
D000328:Adult; D000890:Anti-Infective Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D001711:Biotransformation; D001798:Blood Proteins / Q000378:metabolism; D003404:Creatinine / Q000097:blood / Q000652:urine; D005243:Feces / Q000737:chemistry; D024841:Fluoroquinolones; D018565:Food-Drug Interactions; D000077734:Gatifloxacin; D006207:Half-Life; D006801:Humans; D008297:Male; D010879:Piperazines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D011339:Probenecid / Q000494:pharmacology; D015363:Quinolones / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D012076:Renal Agents / Q000494:pharmacology; D012463:Saliva / Q000378:metabolism
D000890:Anti-Infective Agents; D001798:Blood Proteins; D024841:Fluoroquinolones; D010879:Piperazines; D015363:Quinolones; D012076:Renal Agents; D003404:Creatinine; D000077734:Gatifloxacin; D011339:Probenecid