Absorption of ofloxacin isomers in the rat small intestine

Antimicrobial agents and chemotherapy, 1996

The aim of this work was to examine the mechanism involved in intestinal elimination of the two optical isomers of ofloxacin in the rat. An intestinal segment was isolated in situ and perfused with saline, while drug solution was administered via the carotid artery. Blood samples and intestinal effluents were collected and analyzed by a high-performance liquid chromatography method. We observed saturable and stereoselective intestinal elimination of the ofloxacin enantiomers. The elimination process favored the R-(+) form of the molecule. After a parenteral dose of 20 mg of racemic ofloxacin per kg of body weight, intestinal clearances were 0.23 +/- 0.03 versus 0.30 +/- 0.03 ml/min for S-(-)- and R-(+)-ofloxacin, respectively. Ciprofloxacin and pefloxacin interfered with ofloxacin elimination and significantly reduced the intestinal clearance of S-(-)- and R-(+)-ofloxacin. With concomitant ciprofloxacin, intestinal clearances became 0.13 +/- 0.02 versus 0.17 +/- 0.03 ml/min and 0.14...

Antimicrobial Agents and Chemotherapy, 1991

A study was performed to establish the effect of A13+ and Fe24 cations on the absorption of ofloxacin when it is administered orally at a dose of 200 mg. The study was carried out with nine volunteers, who each received three treatments (A [200 mg of ofloxacin], B [200 mg of ofloxacin plus 11 g of colloidal aluminum phosphate], and C [200 mg of ofloxacin plus 1,050 mg of FeSO41) according to a Latin square design; the washout period was 1 week. The analytical technique was a microbiological diffusion method. The pharmacokinetic parameters were calculated from the cumulative urinary excretion data and from a sigma-minus plot. The total amount of ofloxacin excreted in urine had a mean value of 163.59 + 22.13 mg when ofloxacin was administered alone, 152.41 ± 18.76 mg when it was administered with Al3+, and 146.49 + 14.85 mg when it was administered with Fe2+. No statistically significant differences were found in the F values (fractions of dose absorbed) obtained with ofloxacin alone and ofloxacin plus Al3+ (P = 0.341). When ofloxacin alone was compared with joint administration with Fe24 the value of F decreased 10.85%; this difference is statistically significant (P = 2.623 X 10-2).

Bulletin of Pharmaceutical Sciences. Assiut, 2006

Bioorganic & Medicinal Chemistry, 2002

The interaction between ofloxacin, as a model drug of the fluoroquinolone class, and biomembranes was examined as the possible initial step in a transmembrane diffusion process. Dipalmitoylphosphatidylcholine was used for the preparation of biomembrane models. The influence of environmental conditions and protonation on molecular physicochemical behavior, and hence on the membrane interaction, was investigated by differential scanning calorimetry (DSC). This technique has been shown to be very effective in the interpretation of interactions of drug microspeciations with biomembranes. These findings suggest that the interaction occurred owing to ionic and hydrophobic forces showing how the passage through the membrane is mainly favored in the pH interval 6-7.4. It was demonstrated that a pH gradient through model membranes may be responsible for a poorly homogeneous distribution of ofloxacin (or other related fluoroquinolones), which justifies the in vivo accumulation properties of this drug. DSC experiments, which are in agreement with computational data, also showed that the complexing capability of ofloxacin with regard to Mg ++ or Ca ++ may govern the drug entrance into bacterial cells before the DNA Girase inhibition and could ensure the formation of hydrophobic and more fluid phospholipid domains on the surface of the model membrane. These regions are more permeable with regard to various solutes, as well as ofloxacin, allowing a so-called 'self-promoted entrance pathway'. The combination of experimental methodologies with computational data allowed a further rationalization of the results and opened new perspectives into the mechanism of action of ofloxacin, namely its interaction with lipid bilayers and drug-divalent cation complex formation, which might be extended to the entire fluoroquinolone class. Ofloxacin accumulation within Escherichia coli ATCC 25922 was measured as a function of time. Also in this example, the environmental conditions influenced ofloxacin penetration and accumulation. The in vitro experiments, reported here, show that a suitable balance of hydrophilic and hydrophobic fluoroquinolone properties needs to occur for there to be increased drug permeation. #

Antimicrobial Agents and Chemotherapy, 1987

In 10 volunteers, the pharmacokinetics of ofloxacin {HOE 280, DL 8280; (+)-9-fluoro-2,3-dihydro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-7H-pyrido-[1,2,3-deI benzoxacine-6-carboxylic acid} was determined after administration of 25, 50, 100, and 200 mg intravenously (30-min infusion) as well as 200 and 400 mg orally. Concentrations in serum and urine were measured by high-pressure liquid chromatography. Concentrations in serum following different parenteral ofloxacin dosages demonstrated dose dependency with long biological half-lives of 231 to 267 min. Pharmacokinetic parameters were calculated on the basis of open twoand three-compartment models, which yielded nearly identical results. High volumes of distribution (1.2 to 1.4 liters/kg of body weight) suggested effective diffusion into the extravascular space. High total and renal clearances indicated primarily renal excretion with additional elimination pathways, such as tubular secretion and extrarenal elimination. After oral administration, absorption was excellent, and the absolute bioavailability following 200 mg of ofloxacin could be calculated at >0.95. Maximal concentrations in serum were attained 1.2 to 1.9 h after dosing; areas under the curve increased in proportion to dose between 200 and 400 mg of oral ofloxacin. The amount of known metabolites (demethyl and N-oxide compounds) excreted in urine reached only 4.3% (intravenously) and 4.0% (orally). Transient headaches in some volunteers were the only side effects registered.

Acta poloniae pharmaceutica

Present study was undertaken to evaluate the effect of binders on the bioavailability of the drug. Two formulations of ofloxacin were manufactured with two different binders, i.e. gelatin and starch, which were analyzed by different in vitro tests such as dissolution test using USP apparatus II (paddle method) by using 0.1 M HCl solution. For in vivo studies, blood samples were collected through the heparinized syringe at zero time (before dosing) and at 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 10.0, 12.0, 24.0 hours after the dosing of ofloxacin tablets to 24 rabbits and analyzed by high performance liquid chromatography. Mobile phase consisted of distilled water, acetonitrile and triethylamine (700 : 300 : 1.4, v/v/v). The pH of the mobile phase was adjusted at 2.4 with orthophosphoric acid. The maximum plasma concentration attained after the administration of formulation 1 (containing gelatin) was 7.56 +/- 0.835 microg/mL (the mean +/- SEM) and of formulation 2 (containing starch) was 3.441...

Pharmaceutical research, 2000

The transepithelial transport of levofloxacin was evaluated in the isolated perfused kidney to investigate its renal secretory mechanisms. Levofloxacin was instantaneously administered into the renal artery together with inulin and Evans blue-labeled albumin, and the single-pass dilution curves of the renal venous and urinary outflow were determined in the absence or presence of various compounds. Kinetic parameters were computed based on non-compartment moment analysis. The ratio of fractional excretion to filtration fraction (FE/FF) for levofloxacin was 2.99 +/- 0.18, indicating the involvement of tubular secretion. In the presence of cimetidine and quinolones, the FE/FF of levofloxacin was significantly decreased and the transepithelial mean transit time (Tcell) of levofloxacin was prolonged. The Tcell showed a negative correlation with renal secretion of levofloxacin, while the volume of distribution of levofloxacin showed no correlation. Transport on the brush-border membrane p...

British Journal of Pharmacology, 1995

The stereoselective transport of β‐lactam antibiotics has been investigated in the human intestinal epithelial cell line, Caco‐2, by use of D‐ and L‐enantiomers of cephalexin and loracarbef as substrates. The L‐isomers of cephalexin, loracarbef and dipeptides displayed a higher affinity for the oligopeptide/H+‐symporter in Caco‐2 cells than the D‐isomers. This was demonstrated by inhibition of the influx of the β‐lactam, [3H]‐cefadroxil. By measurement of the substrate‐induced intracellular acidification in Caco‐2 cells loaded with the pH‐sensitive fluorescent dye BCECF (2′,7′‐bis(2‐carboxyethyl)‐5‐(6)‐carboxy‐fluorescein), it was demonstrated for the first time that L‐isomers of β‐lactams not only bind to the peptide transporter with high affinity but are indeed transported. Efficient proton‐coupled transport of L‐β‐lactam antibiotics was also shown to occur in Xenopus laevis oocytes expressing the cloned peptide transporter PepTl from rabbit small intestine. Both cell systems ther...

2019

Pharmacokinetic (PK) behaviour of ofloxacin following single intravenous (iv) and oral administration in goat was evaluated. Ofloxacin was administered @ 5 mg/kg body weight by iv and oral route. Plasma concentration of ofloxacin at pre-scheduled times were processed and estimated by using HPLC. The PK parameters were determined by non-compartmental open model. The therapeutic concentration was achieved in 2.5 min and 45 min and maintained up to 36 h and 8 h following iv and oral administration respectively. The mean AUC, AUMC, t, MRT, Cl and Vd are 58.94 ± 19.43 μg h/ml, 1539.57 ± 724.69 μg h/ml, 15.58 ± 1.87 h, 22.46 ± 2.71 h, 135.60 ± 31.12 ml/h/kg and 2.85 ± 0.74 L/kg respectively following iv administration. The calculated AUC, AUMC, t ka, MRT after oral administration was 11.41 ± 1.13 /h/ml, 221.11 ± 38.44 g/h/ml, 5.404 ± 0.78 h, 16.04 ± 1.19 h. The kinetic behaviour following iv administration is suggestive of entero-hepatic recycling with a secondary peak at 24 h. Followin...

2001

To evaluate the mechanism of renal transport of quinolone antibacterial drugs, we examined the interaction of levofloxacin with p-aminohippurate (PAH) transport systems and the transport of levofloxacin in renal epithelial cells. Methods. Transport of [ 14 C]PAH or [ 14 C]levofloxacin was measured using OK cell monolayers grown on microporous membrane filters. Results. Transcellular transport from the basolateral to the apical side and cellular accumulation of [ 14 C]PAH were inhibited by levofloxacin. Both the initial uptake of [ 14 C]PAH from the basolateral side and the efflux to the apical side were inhibited by levofloxacin. The basolateral-to-apical transcellular transport of [ 14 C]levofloxacin was greater than that in the opposite direction. [ 14 C]Levofloxacin efflux to the apical side was greater than that to the basolateral side. Unlabeled levofloxacin and grepafloxacin inhibited the transcellular transport of [ 14 C]levofloxacin, accompanied by an increase of cellular accumulation. However, neither PAH nor an anion transport inhibitor 4-4Ј-diisothiocyanostilbene-2,2Ј-disulfonic acid (DIDS) affected the basolateral-to-apical transport of [ 14 C]levofloxacin nor its uptake from the basolateral side. Conclusions. These results indicated that levofloxacin inhibits PAH transport across both the basolateral and apical membranes of OK cells, but are not transported via the systems for PAH transport. The existence of a specific transport system for quinolones was indicated in OK cells.