The specific binding of 3H-labeled -y-aminobutyric acid ([3H]GABA) to synaptic plasma membranes from rat brains was inhibited by various quinolonecarboxylic acid derivatives (quinolones), and these inhibitions were concentration dependent. The binding of [3HJmuscimol to GABAA sites was also inhibited. These inhibitory potencies differed widely among the quinolones examined. The Dixon plots showed that a newly developed difluorinated quinolone, -(3-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid hydrochloride], competitively inhibits the receptor bindings of [3H]GABA and [HJmuscimol. In conclusion, our findings suggest that the inhibition of GABA binding to receptors (including uptake sites) in the brain may be involved in the induction of epileptogenic neurotoxicities by quinolones.Quinolonecarboxylic acid derivatives (quinolones) have been used primarily in the treatment of urinary infections. Most of these antibacterial agents have been shown to cause possible neurotoxic effects, such as headache, dizziness, nausea, vomiting, and paroxysmal epilepsy. As indicated by these side effects on the central nervous system and the occurrence of measurable concentrations in the brain after oral or intravenous administration (7,13,14,16), these quinolones are considered to penetrate the blood-brain barrier. However, the mechanism of the quinolone-induced effects on the central nervous system is unknown.The convulsant actions of penicillins and cephalosporins have been related to the reduction of y-aminobutyric acid (GABA) release from nerve terminals or to the inhibition of the binding of GABA to its receptor sites (1, 5, 10). GABA is a major inhibitory neurotransmitter in the mammalian central nervous system. The epileptogenic neurotoxicity of quinolones and the inhibitory effects of penicillins and cephalosporins on GABA receptor binding prompted us to examine the effects of quinolones, including [1-ethyl-6,8-difluoro-1,4-dihydro-7-(3-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid hydrochloride], a newly developed difluorinated quinolone (9) (Fig. 1) Boston, Mass. (+)-Baclofen was supplied from Shionogi & Co., Ltd., Osaka, Japan. Pipemidic acid, ciprofloxacin, norfloxacin, enoxacin, and NY-198 were synthesized in the Central Research Laboratory, Hokuriku Seiyaku Co., Ltd., Fukui, Japan. Nalidixic acid and ofloxacin were kindly supplied by Daiichi Seiyaku Co., Ltd., Tokyo, Japan, and cinoxacin was supplied by Shionogi & Co., Ltd. The purities of these quinolones were found to be more than 99.5% by high-performance liquid chromatography. All other reagents were commercial products of analytical grade and were used without further purification. Distilled, deionized water was used throughout the experiments.Preparation of synaptic plasma membranes. Synaptic plasma membranes were prepared by the method of Zukin et al. (18) from the brains of Sprague-Dawley rats (Nihon Clea, Tokyo, Japan) weighing 230 to 270 g. For the study on sodium-independent (-Na) binding of [3H]GABA or [3H]muscimol, the membrane pell...
Multilamellar vesicles (300-350 nm) were infused into the rat femoral vein at the rate of 4, 40 and 400 nmol phosphatidycholine min-1 for 6 h using [3H]inulin as an aqueous marker. The time courses of blood concentration of vesicles, normalized for infusion rate, were not superimposable, showing the non-linearity of liposome disposition in the blood circulation. These time courses of blood concentration were well fitted by a single Michaelis-Menten equation. On the other hand, the time courses of tissue content could not be so accommodated. Additionally, the observed relationship between the uptake of liposomes by the liver and their clearance from it and other organs differed essentially from a simulation based on Michaelis-Menten type saturable kinetics. Therefore, it is suggested that there is a time-dependent non-Michaelis-Menten type process in the phagocytosis of macrophages in the reticuloendothelial system.
The objective of this study was to examine the AUC dependency of saturable hepatic clearance (CLh) of liposomes and to postulate a mathematical model to describe the characteristics. The AUC dependency of saturable CLh was examined under intravenous rapid administration at various doses. The CLh increased with increasing blood concentration but decreased with the increase of AUC at each dose. In addition, the relationship between AUC and CLh was consistent with that observed in previously reported infusion studies. These experimental data confirm the AUC dependency of saturable CLh of liposomes. A mathematical model was developed for this AUC dependency. The decrease of CLh was described by the uptake amount (X) as follows: CLh = CLm(1-X/Xm), where CLm and Xm represent the maximum uptake clearance and the maximum uptake amount, respectively. The rate equation for uptake was analytically solved as CLh = X/AUC = Xm/AUC(1-exp(CLm/XmAUC)). Uptake clearance can be described by CLm, Xm, and AUC, and so uptake clearance is constant if AUC is constant. These experimental analyses and theoretical considerations show the validity of the AUC-dependent saturable CLh of liposomes.
The objective of this study was to verify the methodology for measuring uptake clearance of liposomes and to characterize kinetically the saturable hepatic uptake of liposomes-through phagocytosis. The correction of vascular space was important in the evaluation of hepatic uptake. The efflux of liposomes from liver was shown to be negligible, by a repeated dose study, and thus, hepatic clearance can be obtained by the hepatic uptake divided by the area under the blood concentration-time curve (AUC). The determinant parameter which describes the saturability of uptake clearance of liposomes, independent of infusion rate, was investigated, using the data of an in-vivo constant infusion study, where infusion rate-dependent saturable hepatic clearance was observed. The mean blood concentration failed to obtain an infusion rate-independent function. On the other hand, the AUC could explain the saturability of hepatic clearance for every infusion rate by a unique relationship. The hepatic uptake amount could also explain this saturability, independent of infusion rate. These kinetic characteristics are inconsistent with Michaelis-Menten type kinetics, therefore a new model is required to describe the saturable hepatic clearance in the disposition of liposomes.
The aim of this study is to develop a kinetic model for the quantitative evaluation of, and to examine dose dependency in liposome degradation in blood circulation in vivo. Multilamellar liposomes labeled with 3H-inulin were administered intravenously into rats and the time courses of blood concentration and urinary excretion of 3H-inulin were measured. The dosages of liposomes were fixed at 1, 5, and 100 mumolPCkg-1. Remarkable saturation was found in the time courses of both blood concentration and urinary excretion. Then a kinetic model for the degradation of liposomes in blood was developed, assuming that the degradation follows the first order rate process for each dose. The model fitted the observed time courses of excreted 3H-inulin well, and dose dependency could be observed in the rate constants for liposome degradation, which are more sensitive than urinary excretion of 3H-inulin. The degradation rate constant correlated well with the uptake rate constant, which suggests the same underlying mechanism for both uptake and degradation. These results indicate the usefulness of kinetic modeling in the quantitative evaluation of liposome degradation in blood circulation in vivo.
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