Rolf Rohwedder

Pharmacokinetics of ciprofloxacin

SummaryThe fluorination of piperazinyl substituted quinolones has led to an interesting development of a series of new broad spectrum antibacterial agents that may be administered orally as well as parenterally and are well tolerated. Norfloxacin was an early compound, later followed by ciprofloxacin, enoxacin, ofloxacin and pefloxacin. In this overview the emphasis will be on the most extensively studied compound including comparisons, where data are available, with norfloxacin and ofloxacin. Enoxacin and pefloxacin will be omitted due to their pattern of side effects, which at present curtail their therapeutic use. More recent substances such as fleroxacin and defloxacin have not been sufficiently investigated to be considered in this context.ZusammenfassungDie Fluorierung von Piperazin-substituierten Chinolonen hat zur Entwicklung einer interessanten Serie neuer Breitspektrum-Antibiotika geführt, die oral und parenteral verabreicht werden können und gut vertragen werden. Norfloxacin wurde bereits früh entwickelt, es folgten Ciprofloxacin, Enoxacin, Ofloxacin und Pefloxacin. In der vorliegenden Übersicht wird die am umfangreichsten untersuchte Verbindung am stärksten berücksichtigt und es werden, soweit verfügbar, Daten von Norfloxacin und Ofloxacin zum Vergleich herangezogen. Wegen ihrer Nebenwirkungs-Profile, die derzeit ihre therapeutische Anwendung einschränken, werden Enoxacin und Pefloxacin übergangen. Für Substanzen jüngeren Datums, wie Fleroxacin und Defloxacin liegen für eine Diskussion in diesem Rahmen noch nicht genügend Untersuchungen vor.

Transintestinal elimination of ciprofloxacin

This study elucidates the routes of elimination of ciprofloxacin and its metabolites in two groups of 5 subjects each, one of healthy volunteers, the other of patients with severe renal failure having a creatinine clearance of 12 ml/min (range 8-16 ml/min). Each subject received one dose of 200 mg ciprofloxacin infused intravenously over 30 min. In an effort to recover the total dose administered, all urine and faeces were collected for the 7 days following dosing. Blood was collected at set intervals after dosing. Serum, urine, and faeces were assayed by high-pressure liquid chromatography for ciprofloxacin and metabolites. The ciprofloxacin serum half-life in healthy volunteers was 3.9 +/- 0.4 h and in patients with marked renal failure 11.2 +/- 2.5 h. The total amount of ciprofloxacin recovered in urine fell by a multiple of 3.4 from 65.3 +/- 10.7% in healthy subjects to 19.0 +/- 15.9% in patients with renal failure, and the metabolites from 12.2 +/- 2.3% in the former group to 5.8 +/- 5.1% in the latter. In contrast, the amount of ciprofloxacin eliminated in faeces increased, by a similar factor, from 11.4 +/- 2.6% in healthy subjects to 37.2 +/- 12.5% in patients with renal failure. The amount of metabolites in faeces increased analogously from 7.3 +/- 1.6 to 26.2 +/- 6.5%. Since ciprofloxacin was administered intravenously and biliary elimination of the drug and its metabolites is negligible, we propose that elimination by faeces is due primarily to transintestinal elimination. This study demonstrates that transintestinal elimination of ciprofloxacin serves as an extrarenal safety factor compensating for reduced elimination by the renal route.

Tolerance of Intravenously Administered Ciprofloxacin

Twelve healthy volunteers received single doses of 200, 300, and 400 mg ciprofloxacin intravenously (30-min infusion). Crystals appeared in the urine of only 1 subject after the 400 mg dose. The crystals appeared in the 0-2 h urine specimen only and were observed immediately upon voiding while the urine was maintained at 37 degrees C. The pH of the urine was 7.3. The event was without untoward consequences to the person as evidenced by urinalysis and blood chemistry. Local skin reactions occurred on the arm of the infusion (cutaneous erythema, itching and burning sensation). The reactions were less after the lowest dose. The reactions started within minutes after the beginning of the infusion and disappeared either during the infusions or immediately after the end of administration. These local reactions were of moderate degree and did not necessitate termination of the infusion.

Tolerance of Ciprofloxacin at Injection Site, Systemic Safety and Effect on Electroencephalogram

The safety of ciprofloxacin, given via 30- and 60-min intravenous infusions at a dose of 300 mg every 12 h for 4 days, was studied in 12 healthy subjects (6 females, 6 males). Local effects of the drug were assessed by frequent examination at the infusion site while systemic safety was determined by haematological and biochemical tests and by careful microscopic examination of the urine for drug crystals and by electroencephalographic studies performed in all subjects before and after dosing. At the site of infusion erythema, itching and a burning sensation developed 10-15 min after onset of infusion in some subjects. These symptoms were slight and did not necessitate termination of the infusions. The rash disappeared in some instances during the infusion and in others within minutes after the end of infusion. The changes usually disappeared, even during the infusion. The incidence of the adverse reactions was not related to the duration of the infusion (30 or 60 min), but was less (frequency and extent) when the anticubital vein was used for infusion rather than when smaller more peripheral veins were employed. Thrombophlebitis occurred after 1 of 96 administrations, and was followed by a return to normal. The electroencephalograms remained normal in all instances. One subject experienced mild nausea of a few hours duration. Only 1 volunteer showed crystalluria; the two such specimens from this subject had the most alkaline pH of all urine samples collected in this study. The probability of crystalluria upon intravenous administration appears not to be higher than after oral administration of ciprofloxacin.

Elimination of Ciprofloxacin and Three Major Metabolites and Consequences of Reduced Renal Function

The pharmacokinetics and elimination of ciprofloxacin and its three major metabolites desethylene ciprofloxacin (M1), sulfonylciprofloxacin (M2), and oxociprofloxacin (M3) were determined in 18 volunteers with normal and varying degrees of reduced renal functions. One dose of 500 mg ciprofloxacin was given orally. Samples were assayed by high-pressure liquid chromatography. Serum concentrations of both ciprofloxacin and its metabolites were only slightly influenced by the renal function. The serum concentrations of the metabolites were less than 10% of the ciprofloxacin levels, even in reduced renal function, and were overlapping within groups of patients arranged according to renal function. Dialysis reduced the serum concentration of the parent compound and its metabolites. The serum half-life of ciprofloxacin in normal renal function was 5.8 +/- 1.2 h; this rose to 10.8 +/- 2.3 h in the group with clearances of 10-30 ml/min. Compared to the latter group, the t1/2 was lower (7.0 +/- 2.9 h) in the patients with terminal renal failure. The period of monitoring has a distinct consequence for the t1/2 of ciprofloxacin. The shorter t1/2 values emanate if monitoring had stopped after 10 or 12 h. A slower gamma-phase of elimination was observed and this was particularly distinct in subjects with renal functions within the normal range. The total renal elimination of the parent compound and its metabolites was approximately 60% over the 48-hour collection period in normal renal function and was reduced by about 20% in the group with clearances within the range of 10-30 ml/min. In renal impairment, there was a shift towards a higher proportion of the dose being eliminated as M2. M1 contributed only up to 2% of the dose in urine. Irrespective of the renal capacity, the amount of M3 recovered in urine was 3-4%.