Pharmacokinetics and tissue penetration of the new fluoroquinolone grepafloxacin

Abstract

A single 400-mg oral dose of grepafloxacin (OPC-17116) was given to each of six healthy male volunteers, and the concentrations of the drug in plasma, cantharides-induced inflammatory fluid, and urine were measured over the subsequent 12 h. The mean peak concentration in plasma of 1.5 g/ml was attained at a mean time of 2.0 h postdose. The mean peak concentration in inflammatory fluid of 1.1 g/ml was attained at a mean time of 4.8 h postdose. The mean elimination half-life in plasma was 5.2 h, and that in inflammatory fluid was 12.7 h. The overall penetration into inflammatory fluid was 180.6% (or 133% if one aberrant result from one volunteer is excluded). Recovery of the drug in urine during the first 24 h postdose was 8.3% of the administered dose. Our results indicate that a once-or twice-daily dosage of grepafloxacin should be adequate to treat systemic infections caused by most bacterial pathogens.Grepafloxacin (OPC-17116) is a new, oral fluoroquinolone which is characterized as having an N-1 cyclopropyl group, a C-5 methyl group, and a C-7 piperazinyl moiety to which a 3-methyl group is attached. In vitro studies suggest that in comparison with the earlier quinolones, grepafloxacin has enhanced activity against gram-positive cocci, including Streptococcus pneumoniae, Enterococcus species, and methicillin-susceptible Staphylococcus aureus (5,8,9,12). It also appears to be more active against anaerobes, particularly Bacteroides species. One study demonstrated activity against chlamydial species, including Chlamydia pneumoniae, that was greater than that of ciprofloxacin or tetracycline (12).The purpose of this study was to investigate the pharmacokinetics of grepafloxacin in healthy volunteers following a single 400-mg dose and to investigate the penetration into inflammatory fluid with a chemically induced blister as a model (13). MATERIALS AND METHODSApproval for this study was obtained from the Hospital Ethical Committee. Six healthy, Caucasian male volunteers with a mean age of 28 years (range, 22 to 37 years), a mean weight of 73.08 kg (range, 60 to 89.4 kg), and a mean height of 1.77 m (range, 1.69 to 1.85 m) were selected. None had a history of atopy or of allergy to antibiotics or had taken any prescribed or over-the-counter medication in the 4 and 2 weeks, respectively, prior to the study. Results of physical examinations, biochemical and hematological profiles, and urinalyses were within normal limits in the 9 days prior to the study. Vital signs, including sitting blood pressure, pulse, respiratory rate, and oral temperature, were checked immediately prior to dosing and after the study. Two 1.5-cm 2 plasters impregnated with 0.2% cantharides were taped to the forearm of each volunteer approximately 12 to 16 h prior to dosing. After an overnight fast, the volunteers were given 400 mg of grepafloxacin (provided by Otsuka Pharmaceutical Company, London, United Kingdom) to be taken orally with 200 ml of water. They fasted for a further 2 h after the dose, at which time they were permitted to have a l...

Modeling of Transfer Kinetics at the Serum-Cerebrospinal Fluid Barrier in Rabbits with Experimental Meningitis: Application to Grepafloxacin

“…The model differs from previous population kinetic models in that not only the partition coefficient but also passive diffusion and active trans- We found a high volume of distribution in the peripheral (tissue) compartment. This is consistent with previous studies (8,13,31) and predictions based on the high lipophilicity of the drug. The average partition coefficient is close to the value obtained by descriptive analysis (16.9 versus 16.0%) (14).…”

Comparative uptake of grepafloxacin and ciprofloxacin by a human monocytic cell line, THP-1

“…[14][15][16][17][18] Pharmacokinetic studies suggested that grepafloxacin was better distributed in tissues than other fluoroquinolone antibiotics, especially in lung 19,20 and in alveolar macrophages. 13 Thus, grepafloxacin is expected to be useful against intracellular pathogens that cause respiratory infections, such as Legionella, Chlamydia, and Mycobacterium species.…”

Grepafloxacin: pharmacokinetics and tissue penetration

“…In an early study using grepafloxacin, six healthy male volunteers (mean age 28 years, mean weight 73 kg) were given a single oral dose of grepafloxacin, 400 mg [2]. The levels of the drug were measured in plasma, in urine and in a cantharidin‐induced inflammatory fluid model.…”