The pharmacokinetics of ciprofloxacin (Bay o 9867) was examined after a single oral dose of 250 mg and a single intravenous dose of 100 mg respectively in six healthy male volunteers in an open, randomized crossover study. Although ciprofloxacin concentrations were measured in serum, plasma and urine by HPLC with fluorimetric detection and by microbiological assay, all pharmacokinetic calculations are based on the highly sensitive HPLC method only. The mean serum concentration of ciprofloxacin peaked approximately 1 h after the oral dose (0.94 mg/l). The elimination half-life was about 4 h and the renal clearance was 4.75 ml/min . kg; both were independent of the route of administration. The total clearance (9.62 ml/min . kg) was about twofold higher than the renal clearance. The volume of distribution of the central compartment was calculated to be 0.161 l/kg and the total volume at steady state was 2.0 l/kg. About 27% of the oral dose was excreted in urine, whereas the urinary recovery of the i.v. dose was 46%. The absolute bioavailability of ciprofloxacin was found to be approximately 60%. Ciprofloxacin appears to follow first-order, three compartment model kinetics.

1 The absorption of ciprofloxacin from different regions of the human gastrointestinal tract was investigated in four healthy males using a remote-controlled drug delivery device (hf-capsule). 2 Significant differences in AUC were observed in the control study (oral administration of ciprofloxacin solution without the hf-capsule = 100%) and after release of ciprofloxacin in the jejunum (geometric mean: 37%), the ileum (mean: 23%), the ascending colon (mean: 7%) and the descending colon (mean: 5%), whereas tmax showed no difference for any of the absorption sites. Ciprofloxacin release in the stomach resulted in the greatest AUC (mean: 140%). Thus, it is concluded that the main absorption site of ciprofloxacin is the upper gastrointestinal tract, up to the jejunum. 3 Differences in presystemic metabolism of known drug metabolites along the gut could be excluded, as the pattern of urinary recovery of desethylene-, sulpho-, and oxociprofloxacin and the parent compound was similar for all drug release sites.

Serum concentrations and urinary excretion of ciprofloxacin were studied in female and male volunteers following a single oral administration of 100 mg, 250 mg, 500 mg or 1000 mg. Serum and urine concentrations increased proportionally to the increasing dose administered but independently of sex. Twenty-five percent of the administered dose was excreted in the urine as unmetabolized ciprofloxacin within the first 24 hours after oral administration. Renal clearance averaged 5 ml/min X kg.

A 200 mg oral dose of ciprofloxacin, norfloxacin or ofloxacin was administered to six healthy male volunteers in a three way cross-over study in order to examine the kinetics in humans in relation to the bactericidal activity in serum and urine. Serum concentrations for ciprofloxacin were similar to norfloxacin and lower than ofloxacin. Despite this fact, ciprofloxacin showed the highest serum bactericidal titers compared to norfloxacin and ofloxacin when serum-resistant Escherichia coli C14 was used as a test organism. These results correlate with observations from timekill curve studies in human whole blood, where ciprofloxacin showed superior bactericidal activity compared to norfloxacin or ofloxacin. The amounts of unchanged drug excreted in urine (48 h period) were found to be 35%, 24% and 77% for ciprofloxacin, norfloxacin and ofloxacin respectively, indicating different excretion kinetics. The volumes of urine excreted in the different collection periods were comparable for the three drugs tested. Mean urine concentrations for ciprofloxacin were higher during the 0 to 4 h collection periods, whereas ofloxacin was excreted into the urine over a longer time period. Measurements of urine bactericidal activity showed that ciprofloxacin had the highest titers during the early collection periods, whereas the prolonged excretion of ofloxacin did not result in higher urine bactericidal titers, compared to ciprofloxacin.

The carcinogenic activity of the two polycyclic aromatic hydrocarbons (PAHs), picene (benzo[a]chrysene) and dibenz[a,h]anthracene (DBA), was determined in NMRI mice by five different experimental protocols in order to find out if picene is a carcinogen as predicted by recent quantum mechanical calculations in contrast to earlier observations which could not confirm any carcinogenic activity of picene. Single s.c. treatment of adult mice with picene or DBA (308 nmol/animal, each) led to the formation of fibrosarcomas in 63.3% of treated animals regardless of the PAH used. Chronic epicutaneous application of both PAHs (total dose 1.36 mumol) to the back of mice resulted in the development of papillomas with a tumor rate of 22% in the case of picene and of 32% in the case of DBA. When newborn mice were s.c. treated once on day 2 of their life with each of the two PAHs (400 nmol/animal), 27.8% of treated animals developed lung adenomas after 40 weeks in the case of picene compared to 92.1% in the case of DBA. Histopathological examination of the tumors in the three experimental models revealed no difference in the type of tumor between picene and DBA. Epicutaneous application of both PAHs (600 nmol/animal) followed by chronic treatment with 12-O-tetradecanoyl-phorbol-13-acetate for 24 weeks led to the formation of papillomas in 93% of animals treated with DBA while picene showed no tumorigenic activity at all. Initiation of tumorigenesis in the two-stage tumor model with 7,12-dimethylbenz[a]anthracene (1 mumol/animal) and chronic treatment with picene (total dose 4.8 mumol) for 24 weeks was equally ineffective in producing tumors in NMRI mice. This rare biological property of picene, which is a complete carcinogen, yet at most a very weak tumor initiator, is explained in terms of its inefficient biotransformation to mutagenic and carcinogenic metabolites as compared to the strong tumor initiator DBA.