Pharmacokinetics and absolute bioavailability of sitafloxacin, a new fluoroquinolone antibiotic, in healthy male and female Caucasian subjects.

1. The aim was to compare the pharmacokinetics of sitafloxacin from a capsule formulation (dose of 500 mg sitafloxacin) and an intravenous (i.v.) formulation infused over 1 h (dose of 400 mg sitafloxacin) in healthy male and female subjects and to estimate the absolute bioavailability of sitafloxacin from the capsule formulation. 2. Following oral administration, sitafloxacin was rapidly absorbed, with a mean maximum concentration in plasma of 4.65 microgml(-1) occuring at median tmax = 1.25 h giving a mean AUC(0-infinity) = 28.1 microg h ml(-1). For the i.v. administration, a mean Cmax = 5.53 microm(-1) occurred at the end of the 1-h infusion with a mean AUC(0-infinity) = 25.4 microg h ml(-1). The mean terminal elimination half-life was 7.0 h (oral) and 6.6 h (i.v.). For the oral and i.v. formulations, the mean total plasma clearance was 296 and 263 mlmin(-1), respectively and the mean volume of distribution was 180 and 150 litres, respectively. 3. Within 48 h post-dose, approximately 61% (range 22-86%) of the administered dose was excreted unchanged in urine following capsule administration, compared with approximately 75% (range 42-101%) following the i.v. formulation. For both formulations, the renal clearance of sitafloxacin (means of 181 and 198 ml min(-1) for the capsule and i.v. doses, respectively) implies active tubular secretion of the drug. 4. The absolute bioavailability of sitafloxacin from the capsule formulation was high at 89%, with a 95% CI of 84-94%. The intersubject variability (CV%) in the sitafloxacin AUC(0-infinity) for the capsule was low at 18.6%. 5. Gender differences in the pharmacokinetics of sitafloxacin were small and would not warrant dose adjustment. 6. The findings show that the capsule formulation offers good oral bioavailability and merits further clinical evaluation of sitafloxacin as an orally effective fluoroquinolone antibacterial.

Synthesis and antibacterial activity of novel pyridobenzoxazine analogues.

A series of novel LVFX (7) analogues bearing 4,4-dialkyl-3-aminopyrrolidines at the C-10 position of pyridobenzoxazine was synthesized and their antibacterial activities, pharmacokinetics and acute toxicities in animals were evaluated. Non-alkylated pyrrolidine derivative 26a showed greater activity than LVFX (7) against gram-positive and gram-negative bacteria including Pseudomonas aeruginosa, but 26a possessed high acute toxicity in mice and unfavorable pharmacokinetics in rats. When compared with 26a, 4,4-dialkylated derivatives 26c, e.g. showed more potent activity against gram-positive bacteria along with an improvement of pharmacokinetics and reduction of acute toxicity. Increases in lipophilicity by alkylation on the pyrrolidine ring resulted in a good influence on the above profiles.

Pharmacokinetics and tolerance of a new fluoroquinolone antimicrobial drug after single oral doses in healthy volunteers.

1. The pharmacokinetics and tolerance of DV-7751a were investigated in healthy male Caucasian volunteers after single oral doses (100, 200, 400 and 800 mg). 2. DV-7751a was rapidly absorbed in the fasted state. The mean maximum concentration in plasma (Cmax) ranged from 0.27 to 1.98 micrograms/ml for the 100-800-mg dose and the mean time to reach Cmax (tmax) ranged from 1.1 to 1.9 h. The terminal half-life ranged from 8.75 to 10.0 h. A good linear correlation (r = 0.974) was found between doses from 100 to 800 mg and the resulting area under the concentration-time curve (AUC). The plasma protein binding of the drug was in the range of 57-65%. 3. Within 48 h, the cumulative urinary excretion of unchanged drug amounted to 22.0-26.8% of the dose administered. Faecal recovery of the drug up to 72 h after the 400-mg dose was about 12% of the dose given. 4. Adverse events thought to be possibly related to the drug included headache, rash, leg cramp, diarrhoea, abdominal pain, CNS depression and dizziness. DV-7751a, however, was well tolerated with no serious adverse events at any doses and all subjects completed the study. No drug crystals were observed in the urine.

(Fluorocyclopropyl)quinolones. 2. Synthesis and Stereochemical structure-activity relationships of chiral 7-(7-amino-5-azaspiro[2.4]heptan-5-yl)-1-(2-fluorocyclopropyl)quinolone antibacterial agents.

A series of novel chiral 7-(7-amino-5-azaspiro[2.4]heptan-4-yl)-8-chloro-1-(2-fluo rocyclopropyl)- quinolones were synthesized as a continuation of a research project of 1-(2-fluorocyclopropyl)-quinolones by considering stereochemical and physicochemical properties of the molecule. Absolute configurations of the 1-(cis-2-fluorocyclopropyl) moiety and the 7-(7-amino-5-azaspiro-[2.4]heptan-5-yl) moiety were determined by X-ray crystallographic analysis. Stereochemical structure-activity relationship studies indicated that 1-[(1R,2S)-2-fluorocyclopropyl] and 7-[(7S)-amino-5-azaspiro[2.4]heptan-5-yl] derivatives are more potent against Gram-positive and Gram-negative bacteria than the other stereoisomers and 7-[(7S)-7-amino-5-azaspiro[2.4]-heptan-5-yl]-8-chloro-1-[(1R ,2S)-2- fluorocyclopropyl]quinolone (33) is the most potent of all stereoisomers. Pharmacokinetic profiles and physicochemical properties of the selected compounds were also examined, and it was found that 33 (DU-6859a) possesses moderate lipophilicity and good pharmacokinetic profiles.

Synthesis and structure-activity relationships of 7-[3-(1-aminoalkyl)pyrrolidinyl]- and 7-[3-1-aminocycloalkyl)pyrrolidinyl]-quinolone antibacterials.

A series of 7-[3-(1-aminoalkyl and 1-aminocycloalkyl)-1-pyrrolidinyl] quinolones have been prepared and their biological properties evaluated. Among them, 1-(S)-aminoalkyl derivatives exhibited potent antibacterial activities against gram-positive and gram-negative organisms. They had moderate lipophilicity and high aqueous solubility compared to their aminomethyl counterparts; e.g., the 3-(1-aminoethyl)-1-pyrrolidinyl compound (83) showed superior pharmacokinetic properties to its aminomethyl counterpart (6).

Regio- and stereoselective synthesis of carbocyclic 2',3'-dideoxy-3'-fluoro nucleosides as potential antiviral agents.

The synthesis and antiviral activity of racemic carbocyclic 2',3'-dideoxy-3'-fluoro nucleosides are reported. Carbocyclic 2',3'-dideoxy-3'-fluoro nucleosides were obtained from the 3-fluoro cyclopentane derivative 4, which was prepared by two methods. The SN2-displacement of the hydroxyl group of (+/-)-(1 beta, 2 alpha, 3 beta, 4 beta)-4-acetamido-2-fluoro-3-hydroxycyclopentylmethyl acetate (1) with Ph3P-I2 followed by tin hydride reduction afforded the 3-fluoroamino alcohol derivative 3. Alternatively, the protected fluoroamino alcohol 3 was prepared by regio- and stereoselective bromo-fluorination of cis-4 beta-acetamidocyclopent-2-enemethyl acetate (5) with hydrogen fluoride-pyridine/N-bromosuccinimide followed by tin hydride reduction to remove the bromine atom. Carbocyclic 2',3'-dideoxy-3'-fluoroguanosine (14) thus obtained was moderately active against herpes simplex virus in vitro.

Fluorocyclopropyl quinolones. 1. Synthesis and structure-activity relationships of 1-(2-fluorocyclopropyl)-3-pyridonecarboxylic acid antibacterial agents.

A series of 1-(2-fluorocyclopropyl)-3-pyridonecarboxylic acids has been prepared. These derivatives are characterized by having a fluorine atom at the 2-position on the cyclopropane ring as the N1 substituent and consist of both cis and trans stereoisomers. Structure-activity relationship studies indicate that the cis derivatives are more potent against Gram-positive bacteria than the corresponding trans counterparts, but the difference in potency against most Gram-negative bacteria is much smaller. The inhibitory effect of compounds 4, 5, 26, 27, 38, and 39 on supercoiling activity of DNA gyrase obtained from E. coli KL-16 correlated with their MICs against the same strain and also depend on their (26, 27, 38, 39) stereochemistry. Introduction of a fluorine atom on the cyclopropyl group resulted in the reduction of lipophilicity compared with the corresponding nonfluorinated quinolones.

Modification of the cysteamine side chain of thienamycin. III.

Thienamycin derivatives (4) having a cyclic amidine moiety at the C-2 position were prepared. The susceptibility to renal dehydropeptidase-1 and the antimicrobial activity of these compounds were determined. Their structure-activity relationships are also discussed.

Modification of the cysteamine side chain of thienamycin. II.

A new type of thienamycin derivatives (3a-3j, 4a, 4b), having a monothioacetal or a thioacetal side chain at the C-2 position was prepared, and the susceptibility to renal dehydropeptidase-1 (DHP-1) and the antimicrobial activity of these compounds were determined. The structure-activity relationships of these derivatives are also discussed.

Synthesis and antibacterial activities of optically active ofloxacin.

Two optically active (100% enantiomeric excess) isomers of ofloxacin [(+/-)-ofloxacin; DL-8280; (+/-)-9-fluoro-2,3-dihydro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-7 H-pyrido[1,2,3-de] [1,4] benzoxazine-6-carboxylic acid] were prepared by use of their optically resolved synthetic intermediates. One of the isomers, (-)-ofloxacin, was 8 to 128 times more potent in inhibiting the multiplication of gram-positive and gram-negative bacteria than the other, (+)-ofloxacin, and approximately two times more active than the racemate, (+/-)-ofloxacin.