The pharmacokinetic and pharmacodynamic properties of FK613, a novel indolyl piperidine derivative, were investigated after oral administrations of 5, 10 and 20 mg in hard gelatin capsules to healthy male volunteers. FK613 was rapidly and almost completely absorbed, and >89% was recovered in the urine as the unchanged form. The urinary excretion of FK613 was linearly correlated with plasma concentration and its low water solubility was the main concern regarding the safety. In another experiment using a double-blind crossover design, in which 0 (placebo), 5 and 20 mg FK613 were administered to determine the plasma concentration-effect relationship, suppression of the intradermal histamine-induced skin reaction by FK613 was observed. Thus, the maintenance of a plasma concentration of FK613 in the range of 80-250 ng center dot ml-1 was recommended to ensure the suppression of histamine-induced wheal by >50% and not to exceed the solubility in urine. To achieve this, a new hydrogel-type formulation of FK613 was developed, with the aim both of delaying its absorption, so as to suppress the sharp rise in plasma concentration, and of maintaining the effective concentration for a longer period of time. This formulation was administered after meals at the doses of 20, 30, 40, 50 and 60 mg, and at repeated doses of 40 mg twice daily for 6.5 days to evaluate the pharmacokinetics and safety in healthy subjects. The area under the plasma concentration curve increased linearly with dose, whereas maximum plasma concentration (Cmax) tended to peak as dose increased, indicating the desirable properties of this formulation. Although Cmax exceeded 250 ng/ml at doses of 30 mg or more, no urinary crystal formation was observed on careful inspection of urine.
Its chemical nomenclature is (6 R, 7 R) 7 [(Z)-2-(2-amino-4-thiazolyl)-2 (carboxymethoxyimino)-acetomido]-8-oxo-3 vinyl-5-thia-1-azabicyclo-[4,2,0]-octo-2-ene 2-carboxylic acid. Unlike conventional oral cephalosporins and penicillins, FK027 is stable to various ƒÀ-lacta mases and has a broad spectrum of antibacterial activity against gram-positive and gram-nega tive organisms, especially gram-negative bacilli. The time to reach maximum serum concentra tion of FK027 after oral dosing 1) was 3.8 to 4.0 hours, and the apparent elimination half-life was as long as 2.3-2.5 hours. The serum concentra tions were prolonged. The excretion of the unchanged drug in the 24-hr urine was 21-28%. These oral studies suggest that FK027 is gradual ly absorbed after oral dosing and slowly excreted in the urine. However, the systemic bioavailabil ity of FK027 which is very important for investi gating the pharmacokinetics of the drug after oral dosing has not been elucidated. In this study, we investigated the pharmaco kinetics of FK027 in 6 healthy male volunteers after intravenous injection both without and with probenecid which is known to inhibit renal tubular secretion of antibiotics 2)3)4), and discussed the systemic bioavailability after oral dosing. Materials and Methods Six healthy male volunteers between 29 and 49 years of age (mean:40 years) and weighing 55
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