Chemical formula: C₂₁H₂₀FN₃O₆S Molecular mass: 461.46 g/mol PubChem compound: 65947
In vitro, prulifloxacin has shown to be active towards a wide range of Gram-positive and Gram-negative strains. Prulifloxacin exerts its antibacterial activity by the selective inhibition of the DNA-gyrase, an essential enzyme present in bacteria and involved in duplication, transcription and repair of DNA.
Prulifloxacin is a wide spectrum antibacterial agents belonging to the fluoroquinolone group and provided with high efficacy. After oral administration, prulifloxacin is absorbed by the gastrointestinal tract and immediately turned into ulifloxacin, its active metabolite.
The antibiotic resistance to prulifloxacin (like to the other fluoroquinolones) is commonly due to spontaneous mutations in bacterial DNA-gyrase. Cross-resistance to other fluoroquinolones is observed in vitro.
Due to peculiar mechanisms of resistance of fluoroquinolones, there is no cross-resistance between prulifloxacin and antibiotics of different classes, and prulifloxacin can therefore prove efficacious even in the presence of bacteria strains resistant to aminoglycosides, penicillins, cephalosporins and tetracyclines.
They were defined on the basis of NCCLS antibacterial activity data and product pharmacokinetic parameters. The following breakpoints are suggested: Susceptible: MIC ≤1 g/ml, Intermediate: MIC >1 to <4 g/ml, Resistant: MIC ≥4 g/ml.
Prulifloxacin is the pro-drug of the active metabolite, ulifloxacin.
Prulifloxacin is rapidly absorbed in humans (Tmax = about 1h) and turned into ulifloxacin; after a 600 mg single administration, the mean plasma peak of ulifloxacin is 1.6 μg/ml and the AUC is 7.3 μg*h/ml. At the steady-state, which is reached within 2 days from the beginning of treatment after single daily administrations, Cmax and AUC are 2.0 μg/ml and 7.6 μg*h/ml, respectively. Ingestion of food delays and slightly reduces the plasma peak concentration of ulifloxacin, but does not modify the AUC.
In humans, the lung/plasma ratio of prulifloxacin mean concentration increases with time. After 24 hours, the mean concentrations maintained by the active metabolite ulifloxacin in tissues are 5 times higher than those in plasma, thus confirming the results obtained in animals, where ulifloxacin concentrations in lung and kidney have proved to be higher than in plasma (1.2–2.8 times and 3-8 times, respectively).
Similarly, tissues penetration data of ulifloxacin in human paranasal sinus showed AUCs ratios between tissues and plasma of 3.0 for ethmoides and 2.4 for turbinates.
In humans, the protein binding assessed both in vitro and ex vivo, is equal to approx. 50%, regardless of the drug concentration.
The weak ulifloxacin concentration found in the cerebrospinal fluid after i.v. administration in dog and repeated p.o. administration in humans, shows that ulifloxacin hardly crosses the blood-brain barrier.
The metabolic profile of prulifloxacin in animals and humans is comparable. Studies in animals have shown that the prulifloxacin metabolism begins during the intestinal absorption and is completed with its passing through the liver.
Apart from transformation into ulifloxacin, other minor metabolites have been identified, such as the diolic form and some derivatives as glucuronide, oxo-derivative and ethylendiamine derivatives; the concentration and activity of which are negligible compared to the active substance.
In-vitro studies have not shown significant interactions with the P-450 cytochrome isoenzymes except for a slight inhibition of CYP1A1/2, which results in a small reduction of the theophylline clearance. As methylxanthines, and theophylline in particular, are the main substrate for the isoenzyme CYP1A1/2, the level of interaction with other isoenzyme substrates (see warfarin) may only be considered inferior.
The half-life of the active metabolite, ulifloxacin, is about 10 hours, after both single and repeated administration at the steady-state in humans, ranging in animals (rats, dogs and monkeys) between 2 and 12 hours.
In humans, studies with the labelled product have shown that the elimination occurs mainly through the faeces. The radioactivity found in urine and faeces after oral administration of 600 mg, totally amounts to approximately 95%. These results confirm what previously showed by studies carried out in animals (rats, dogs and monkeys).
The quantity of ulifloxacin excreted in urine is equal to 16.7% of the administered dose on a molarity basis and the ulifloxacin renal clearance is about 170 ml/min
The renal elimination of ulifloxacin occurs by glomerular filtration and active secretion.
The pharmacokinetic profile of prulifloxacin in elderly patients has been shown to be similar to adults, with no variations due to age, and therefore no dosage modification have been thought necessary in elderly patients.
In patients with mild or moderate renal impairment, after oral administration of 600 mg prulifloxacin, the mean plasma peak of ulifloxacin reaches values included between 1.30 and 1.62 µg/ml. AUC values range between 13.71 and 23.33 µg*h/ml and the half-life shows to be included between 12.3 and 32.4 hours. Compared to healthy volunteers, the ulifloxacin renal clearance decreases according to the insufficiency level.
The main target organs in repeated dose toxicity studies were articular cartilage, kidneys, gastro-intestinal tract and liver.
No toxic effects have been observed on articular cartilage (young dogs) up to doses 3 times higher than the therapeutic one; for liver (dogs) and kidney (dogs and rats) no toxic effects have been observed up to doses 6 and 10 and 12 times higher than therapeutic dose, respectively. The drug did not prolong the QT interval in vivo and did not show inhibiting effects on the retarded rectifying current of potassium (HERG) in vitro.
Reproductive toxicity studies did not show teratogenicity and effects on fertility or development of embryo and fetus were only observed in association with maternal toxicity.
Standard genotoxicity testing with prulifloxacin showed positive effects in some in vitro tests in mammalian cell cultures but was negative in vivo and in bacteria. The effects are considered related to the inhibition of topoisomerase II in high concentrations. Carcinogenic potential. Prulifloxacin was not carcinogenic in a medium-term initiation-promotion experimental model. Long-term carcinogenicity tests were not performed.
Prulifloxacin showed to be devoid of antigenic effects.
Prulifloxacin has induced phototoxic reactions, although in comparative studies in animals its phototoxic activity has shown to be lower than other fluoroquinolones used (ofloxacin, enoxacin, pefloxacin, nalidixic acid and lomefloxacin). Many quinolones are also photomutagenic/photocarcinogenic, which can not be excluded for prulifloxacin.
After repeated oral administrations of 3000 mg/kg/die in rats, a far higher dosage than the therapeutic dose in humans, prulifloxacin has caused crystalluria by ulifloxacin precipitation.
Studies carried out in dogs have shown that prulifloxacin does not cause significant modifications in the electrocardiogram. In particular, no changes in the QTc have been observed, either after single intravenous administration in the anaesthetised dog, or after oral administration for 6 months in the conscious dog, at all the administered doses. In vitro studies have confirmed the absence of inhibiting effects on the retarded rectifying currents of potassium (HERG).
As other fluoroquinolones, prulifloxacin has caused arthropathy only in young animals.
In monkeys, oral doses of 26.4 or 58.2 mg/kg/die of prulifloxacin once a day for 52 weeks have not caused adverse effects related to the treatment on the ocular function or morphology.
Ulifloxacin doses up to 10 mg/kg/die administered intravenously once a day for 14 consecutive days have not induced rhabdomyolysis in rabbits.
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