Antibacterial evaluation of a collection of norfloxacin and ciprofloxacin derivatives against multiresistant bacteria.

The objective of this study was to analyse an array of ciprofloxacin and norfloxacin derivatives in order to determine those with good activity against bacteria that already present fluoroquinolone resistance associated with mutations in the gyrA and/or parC genes. Four norfloxacin and 20 ciprofloxacin derivatives were synthesised and tested against quinolone-susceptible and -resistant Escherichia coli, Acinetobacter baumannii, Stenotrophomonas maltophilia and Staphylococcus aureus strains using a microdilution test. Among the derivatives, the 4-methyl-7-piperazine ciprofloxacin derivative showed a minimum inhibitory concentration for 50% of the organisms that was 16- and 8-fold lower than ciprofloxacin for A. baumannii and S. maltophilia, respectively. When the methyl group at position 4 in the piperazine ring was substituted by ethyl, butyl or heptyl groups, activity against A. baumannii steadily decreased. The 7-(4-methyl)-piperazine ciprofloxacin derivative (UB-8902) showed very good activity against these multiresistant microorganisms including A. baumannii and S. maltophilia.

Intrinsic absolute bioavailability prediction in rats based on in situ absorption rate constants and/or in vitro partition coefficients: 6-fluoroquinolones.

A preliminary study attempting to predict the intrinsic absolute bioavailability of a group of antibacterial 6-fluoroquinolones-including true and imperfect homologues as well as heterologues-was carried out. The intrinsic absolute bioavailability of the test compounds, F, was assessed on permanently cannulated conscious rats by comparing the trapezoidal normalized areas under the plasma concentration-time curves obtained by intravenous and oral routes (n = 8-12). The high-performance liquid chromatography analytical methods used for plasma samples are described. Prediction of the absolute bioavailability of the compounds was based on their intrinsic rat gut in situ absorption rate constant, k(a). The working equation was: where T represents the mean absorbing time. A T value of 0.93 (+/-0.06) h provides the best correlation between predicted and experimentally obtained bioavailabilities (F' and F, respectively) when k(a) values are used (slope a = 1.10; intercept b = -0.05; r = 0.991). The k(a) values can also be expressed in function of the in vitro partition coefficients, P, between n-octanol and a phosphate buffer. In this case, theoretical k(a) values can be determined with the parameters of a standard k(a)/P correlation previously established for a group of model compounds. When P values are taken instead of k(a) values, reliable bioavailability predictions can also be made. These and other relevant features of the method are discussed.

Pharmacokinetics, bioavailability and absorption of flumequine in the rat.

The study demonstrates that the oral extent of bioavailability of flumequine in the rat, relative to the intravenous injection, is complete (0.94 +/- 0.04) and not significantly different from that found by the intraduodenal route (0.95 +/- 0.04). The rate of oral bioavailability, however, is slow (ka = 1.20 +/- 0.07 h-1; Tmax = 2.0 h), but enough to maintain plasma levels above the minimal inhibitory concentration of the most common pathogens for an extended period of time (about 10 h). The reason for the oral absorption slowness could be a slow gastric emptying, an adsorption to the gastric mucosae, a precipitation in the gastric medium or any other feature concerning the stomach as the intraduodenal administration is very quick (kid = 38.1 +/- 4.7 h-1; Tmax = 0.05 h). A possible precipitation of flumequine cannot be discarded as the solubility of flumequine is very low in the pH range of 3 to 6 (mean pH values for rat stomach and rat intestine, respectively; T.T. Kararli, Biopharm. Drug Dispos. 16 (1995) 351-380). Flumequine was shown to be not substantially excreted in bile (2-3% of the dose). Surprisingly, plasma levels and AUC values found for animals with interrupted bile flow always surpass those found for animals with enterohepatic circulation. This could be due to experimental model features, which might bias plasmatic flumequine concentrations if the homeostatic equilibrium of the animal is not completely restored due to the volume reduction induced by biliary extraction.

Pharmacokinetics of liposome-encapsulated meglumine antimonate after intramuscular and subcutaneous administration in dogs.

Controlling canine leishmaniasis may reduce the incidence of human leishmaniasis, which affect immunocompromised persons, especially those with human immunodeficiency virus infection. Thus, the pharmacokinetics of liposome-encapsulated meglumine antimonate (LMA) in dogs was studied after intramuscular (I.M.) and subcutaneous (S.C.) administration. Serum concentration-time data for both forms of administration were best described by a triexponential open model. The absorption phase showed statistically significant differences between I.M. and S.C. administrations (K01(I.M.) = 0.046/min, K01(S.C.) = 0.025/min). The first phase of decrease of plasma concentrations showed a longer half-life for S.C. than for I.M. administration, with the delay being caused by the slow absorption process after S.C. injection. Mean terminal phase half-lives after administration of I.M. and S.C. were 904.1 min and 637.4 min, respectively. Peak plasma concentrations after administration of I.M. (Cmax = 43.8 microg/ml) and S.C. (Cmax = 24.9 microg/ml) were detected at 42.8 min and 79.8 min, respectively. Urinary excretion of antimony for both routes surpassed 80% during the first 6 hr, with the rest of the drug being excreted slowly over the following 18 hr. The results obtained with this formulation suggest that for treating canine leishmaniasis, it would be more advisable to inject LMA intramuscularly if we assume that the significantly higher Cmax observed after I.M. administration is more relevant to dog's clinical outcome than is maintenance of concentrations over longer periods.

Structure-absorption relationships of a series of 6-fluoroquinolones.

The physicochemical constants and some structural parameters (topological, steric, and electronic) of eight third-generation monofluorate quinolones (six uncommercialized and two used clinically [ciprofloxacin and enrofloxacin]) were determined: pKa, intrinsic solubility (S0), chromatographic capacity factor, partition coefficient (P), valency molecular connectivity, molecular volume, molecular surface area, dipolar moment, and charges associated with each atom of the molecule. The apparent intestinal absorption rate constants (K(abs)) in rat (in vivo perfusion) and the MICs at which 90% of the isolates are inhibited (MIC90s) against 100 Escherichia coli strains were also determined. We sought to establish simple nonlinear and multiple linear correlations between K(abs), on the one hand, and lipophilic parameters and other physicochemical and structural parameters estimated. Of the nonlinear functions examined, the hyperbolic had the best correlation between K(abs) and P, which was in accordance with the Wagner-Sedman (J. G. Wagner and A. J. Sedman, J. Pharmacokinet. Biopharm. 1:23-50, 1973) equation, whereas, after application of the stepwise multiple linear regression method, a multiple linear correlation with some predictive value could be established only between K(abs) as a dependent variable and log P and log S0 as independent variables. In conclusion, the K(abs) and MIC90 of the quinolone CNV 8902 suggest that it is a sufficiently interesting compound to warrant the investigation of its potential therapeutic use orally.

Effects of ethanol on intestinal absorption of drugs. I. In situ studies with ciprofloxacin analogs in normal and chronic alcohol-fed rats.

The effect of chronic alcohol intake on the intestinal absorption of seven compounds belonging to a homologous series (ciprofloxacin derivatives) was evaluated using an in situ rat gut technique that measures the intrinsic absorption rates of the compounds both in control and chronic alcohol-fed rats. For chronic alcohol treatment, the animals were fed a liquid diet containing ethanol (36% of calories), whereas an isocaloric diet was given to the pair-fed control animals. The biophysical absorption model, relating the intestinal absorption rate constants and partition indexes of the tested compounds, was then established either for control or alcohol-fed animals. Differences were analyzed and tentatively interpreted on the basis of general diffusion principles. Results revealed that, in chronic alcohol-fed animals, hydrophilic homologs are absorbed at a significantly faster rate than in control ones, whereas lipophilic homologs do not change their absorption rate relative to controls. Results demonstrate that the bulk polarity of the microvillous lipoidal membrane is enhanced by chronic ethanol intake, whereas basic features of the aqueous boundary layer are not altered. These observations suggest that the physicochemical properties of the compounds are an important factor in explaining the influence of chronic alcohol intake on passive intestinal absorption of xenobiotics. The possible practical implications of our results are discussed from a speculative view-point.

Biophysical models as an approach to study passive absorption in drug development: 6-fluoroquinolones.

A preliminary study attempting to assess and explain the intestinal absorption of a series of antibacterial 7-piperazinyl-6-fluoroquinolones is presented. The synthesis, n-octanol partition coefficients, intrinsic rat gut in situ absorption rate constants, and in vitro antibacterial activity data found for these homologous compounds are described. A fluorimetric, reverse-phase HPLC method was performed for the quantification of the quinolones in absorption and partition samples. Equations based on two classic biophysical absorption models are given for predicting the intrinsic absorption features of the series according to the partition data or merely single structural parameters. In situ absorption rate constants were found to increase by a factor of 9.7-13.5 for moderately lipophilic derivatives relative to the simplest compound, while antibacterial activity decreased only by a factor of 4. In vivo absorption tests with two representative members of the series were carried out and the results showed a good accordance with those found in situ. This makes these compounds or related ones with similar partition features excellent candidates for further pharmacokinetic and pharmacological testing. The study can serve as an example of how to prevent potential absorption problems associated with the development of new drugs.

Influence of the chromatographic capacity factor (log k') as an index of lipophilicity in the antibacterial activity of a series of 6-fluoroquinolones. Relationship between physico-chemical and structural properties and their hydrophobicity.

The aim of this study was to establish the influence of lipophilicity on the antibacterial activity (log 1/MIC50) of 22 fluoroquinolones and to assess the influence of their electronic, steric and topological properties on their hydrophobicity. The lipophilicity of the compounds, expressed as the chromatographic capacity factor (log k'), was determined by ion-pair reversed-phase HPLC. On the basis of the mathematical models developed, an attempt was made to confirm the mechanism of interaction of the quinolones with DNA-gyrase proposed previously.

Intestinal absorption of a series of 6-fluoquinolone derivatives: a comparative study.

The intestinal absorption rate constants of the five 6-fluoquinolones (norfloxacin, ciprofloxacin, pefloxacin, CNV 8802 and CNV 8804), have been estimated in the rat (n = 5) by means of an "in situ" intestinal perfusion method. Remaining 6-fluoquinol one concentrations in the perfusion liquid at fixed time (15, 30, 45, 60, 75, 90 and 120 minutes) were determined using a HPLC procedure with UV detection. Absorptions rate constants were estimated according to first order kinetics. A simple non-linear correlation between Ka and log K' on the one hand and a multiple linear correlation between Ka and the structural theoretical parameters: molar volume, dipolar moment and the charge associated to nitrogen 18 on the other, were performed. Only a correlation between Ka values as dependent variable versus dipolar moment and molecular volume values has been obtained, but this correlation is not statistically significant (p = 0.1808) and not accurate enough to have predictive value.