No 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...

Because of the increasing availability of human liver samples we now have a greater ability to predict in vivo drug disposition and pharmacokinetics in man from in vitro metabolic and binding studies. Firstly, we review several successful attempts to predict in vivo metabolic clearances in experimental animals and humans from in vitro biochemical parameters such as plasma protein binding and hepatic metabolism, based on anatomically and physiologically realistic pharmacokinetic models. Despite the success of this approach, however, there are still some difficulties in predicting in vivo hepatic metabolism in man using in vitro human liver samples due to the large inter‐individual differences arising from polymorphism (intrinsic variability) or differences in enzyme activity (extrinsic variability) due to the conditions under which liver samples have been kept. We propose a possible method to overcome these errors resulting from inter‐individual differences by applying the concept of a scaling factor. In the kinetic models used in prediction, we often make a number of assumptions, e.g. rapid equilibrium between the blood and hepatocytes, availability of only the unbound drug for uptake and elimination, and homogeneous distribution of enzymes along the path taken by the blood in the liver. However, recent evidence suggests that these assumptions are not necessarily valid. As examples involving the first and second assumptions, respectively, there is the plasma‐membrane‐permeability‐limited metabolism of a high‐clearance drug, 4‐methylumbelliferone, and the albumin‐mediated uptake of amphiphatic drugs. The multiple‐indicator dilution method (MID) is useful for estimating the membrane permeability of drugs in liver perfusion systems where the spatial organization and cell polarity of the liver are maintained. If the aforementioned factors are taken into consideration and membrane permeabilities using human hepatocytes and/or subcellular fractions such as microsomes are measured under conditions close to those in vivo, much more reliable predictions of drug hepatic clearance in man may become possible.

The tolerance and pharmacokinetics of fleroxacin were studied in healthy male adult volunteers. The peak serum concentrations of unchanged fleroxacin were about 1.5, 3 and 5 mg/l at 1-2 h after single oral doses of 100, 200 and 400 mg, respectively. The apparent serum elimination half-life was about 10 h, independent of the dose. Fleroxacin, demethyl fleroxacin and fleroxacin N-oxide excreted in urine over 3 days accounted for about 75%, 5% and 5%, respectively, of the doses. The urine concentrations of unchanged drug were dose-related; the mean concentrations, sustained over 24 h, were about 50, 100 and 150 mg/l after 100, 200 and 400 mg doses, respectively. Food intake did not significantly influence the serum concentration and urinary excretion. Steady state serum concentrations were achieved from day 3 onwards by repeated doses of twice-a-day dosage regimen and were 2-4 and 5-9 mg/l after 200 and 400 mg bid, respectively. The mean concentrations of unchanged drug in urine were about 200 and 300 mg/l at the respective dosages. The pattern of urinary metabolites was not changed by repeated doses and 90% of repeat doses was recovered in urine, including metabolites. The serum protein binding of fleroxacin was 32%. The saliva concentration was 40% of the total serum concentration or 60% of the free serum concentration. The faecal recovery over 3 days was 3% of the dose following a single 200 mg dose after a meal. The unchanged drug concentrations in faeces during 400 mg repeated dosing were 100-150 mg/kg. No severe dose-related side-effects were observed during the study.

Imidafenacin (IM), 4-(2-methyl-1H-imidazol-1-yl)-2,2-diphenylbutanamide, is a newly synthesized antimuscarinic drug developed for the treatment of overactive bladder. To predict clinically relevant drug interactions in the metabolism of IM, the paper investigated: (1) the major enzymes responsible for the metabolism of IM, (2) the effects of concomitant drugs on the inhibition of metabolism of IM, and (3) the effects of IM and its metabolites on the inhibition of human cytochrome P450 (CYP). The elimination of IM and production of oxidative metabolites were mainly catalysed by recombinant CYP3A4, and the elimination of IM by human liver microsomes (HLM) was markedly inhibited by co-incubation with ketoconazole. The production of the N-glucuronide metabolite was only catalysed by recombinant UGT1A4. Clinically established CYP3A4 inhibitors including itraconazole, ketoconazole, erythromycin and clarithromycin inhibited the elimination of IM in HLM. IM and its major metabolites did not affect the activities of CYP enzymes in vitro. The results suggest that the major enzymes responsible for the metabolism of IM are CYP3A4 and UGT1A4, and oxidative metabolism of IM is reduced by concomitant administration of CYP3A4 inhibitors. In contrast, IM and its metabolites have no inhibitory effect on the CYP-mediated metabolism of concomitant drugs.