Single- and multiple-dose pharmacokinetics of AM-1155, a new 6-fluoro-8-methoxy quinolone, in humans

Abstract

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 g/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.AM-1155 [(Ϯ)-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(3-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid sesquihydrate] is a new 6-fluoro-8-methoxy quinolone (Fig. 1) being tested in clinical trials. It has potent and broad antimicrobial activity against gram-positive and gram-negative aerobes, anaerobes, and mycobacteria (3,4,21,23). It is more potent than ciprofloxacin and ofloxacin and is comparable to sparfloxacin and tosufloxacin against gram-positive bacteria and anaerobes in vitro; it also has activity comparable to those of ciprofloxacin and sparfloxacin against gram-negative bacteria. Pharmacokinetic studies with laboratory animals demonstrated that this drug was rapidly and completely absorbed from the gastrointestinal tract, well distributed to various tissues except the brain, and principally excreted into the urine (13).The pharmacokinetics of AM-1155 was examined in healthy humans. The parameters studied included the serum drug concentration-time profiles, urinary excretion of unchanged drug after the administr...

CE‐ECL detection of gatifloxacin in biological fluid after clean‐up using SPE

“…This drug offers several advantages over previous antibiotics, including enhanced in vitro activity against clinically important pathogens and improved pharmacokinetics and pharmacodynamics characteristics, which may improve patient outcomes against certain bacterial pathogens, especially penicillin-resistant Streptococcus pneumoniae. The absolute bioavailability of gatifloxacin is 96%, with mean peak plasma concentration of 3.1-3.6 mg/mL usually occurring 1-2 h after the ingestion of a 400 mg therapeutic dosage [1][2][3].…”

“…This drug offers several advantages over previous antibiotics, including enhanced in vitro activity against clinically important pathogens and improved pharmacokinetics and pharmacodynamics characteristics, which may improve patient outcomes against certain bacterial pathogens, especially penicillin-resistant Streptococcus pneumoniae. The absolute bioavailability of gatifloxacin is 96%, with mean peak plasma concentration of 3.1-3.6 mg/mL usually occurring 1-2 h after the ingestion of a 400 mg therapeutic dosage [1][2][3].So far, some methods such as HPLC-UV [4][5][6][7], HPLCfluorimetry [6,8] [20] have been developed for the analysis of gatifloxacin in pharmaceutical preparation, biological fluid and animal tissue. Among these, HPLC [4,6,8,9] based strategies have been most universally used for the determination of this drug in biological samples since the complex matrix may severely interfere in the analysis if effective separation process is absent.…”

Competitive inhibition of renal tubular secretion of ciprofloxacin and metabolite by probenecid

“…Blood samples were taken before the start of the ciprofloxacin infusion, 10 and 20 min after the start of infusion, at the end of infusion, and 5, 10, 20, 30, 45, 60 and 90 min and 2, 3,4,5,6,8,10,12,16,24,30,36 and 48 h after the end of the infusion. The samples were centrifuged immediately.…”

“…Probenecid has been reported to inhibit active transport of both anionic and cationic drug molecules at various sites in the body [3][4][5]. Furthermore, it is well known to decrease the renal secretion of numerous quinolones such as gatifloxacin [6],levofloxacin [7,8],norfloxacin [9],fleroxacin [10] and enoxacin [11]. Moxifloxacin and sparfloxacin are not affected by probenecid [12,13].…”

Stability indicating square-wave stripping voltammetric method for determination of gatifloxacin in pharmaceutical formulation and human blood

“…1,2 Its absolute bioavailability is 96%, with mean peak plasma concentration of 3.1 to 3.6 µg mL -1 usually occurring within 1.0 to 2.0 h after administration of an oral single dosing of a 400 mg gatifloxacin. [2][3][4] It undergoes limited biotransformation in humans with less than 1% of the dose excreted in the urine as ethylenediamine and methylethylenediamine metabolites. 2 Various instrumental analytical methods have been described for assay of gatifloxacin in bulk form, pharmaceutical formulation and biological fluids.…”