Intestinal Absorption Characteristics of Sparfloxacin.

Yamaguchi, Toshikazu; Yokogawa, Makiko; Sekine, Yutaka; Hashimoto, Masahisa

doi:10.2133/dmpk.6.53

Cited by 10 publications

(6 citation statements)

References 5 publications

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“…Thus, the effect of the A13+ ion on absorption of LVFX in rats was investigated further by using the in situ ligated loop method, in which the pH of the drug solution was adjusted to 6.5. It was reported that sparfloxacin was transported in part by a common dipeptide carrier-mediated system in rats (30). We reported previously that LVFX could be absorbed from rat intestine not only by passive diffusion but also by the active carrier-mediated transport system which showed higher affinity to amino acids than to dipeptides (27).…”

Section: Discussionmentioning

confidence: 86%

Mechanistic study of inhibition of levofloxacin absorption by aluminum hydroxide

Tanaka¹,

Kurata²,

Fujisawa³

et al. 1993

Antimicrob Agents Chemother

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The mechanisms of reduction in absorption of levofloxacin (LVFX) by coadministration of aluminum hydroxide were studied. The partition coefficient of LVFX (0.1 mM) between chloroform and phosphate buffer (pH 5.0) was reduced by 60 to 70% with the addition of metal ions such as Cu2e, A13+, and Fe2' (0.8 mM), which indicated the formation of LVFX-metal ion chelates. However, there was no significant difference in absorption from rat intestine between the synthetic LVFX-AI3+ (1:1) chelate (6.75 mM) and LVFX (6.75 mM) in an in situ recirculation experiment. On the other hand, AM(NO3)3 (1.5 mM) significantly inhibited the absorption of LVFX (1.5 mM) by 20%o of the control in the in situ ligated loop experiment, in which partial precipitation of aluminum hydroxide was observed in the dosing solution. Data for adsorption of LVFX and ofloxacin (OFLX) from aqueous solution by aluminum hydroxide were shown to fit Langmuir plots, and the adsorptive capacities (r.,) and the K values were 7.0 mg/g and 1.77 x 14 M-1 for LVFX and 7.4 mglg and 1.42 x 104 M'1 for OFLX, respectively. The rate of adsorption of several quinolones (50 ,uM) onto aluminum hydroxide (2.5 mg/ml) followed the order norfloxacin (NFLX) (72.01%) > enoxacin (ENX) (61.0%) > OFLX (47.2%) LVFX (48.1%). The elution rate of adsorbed quinolones with water followed the rank order LVFX (17.9%) OFLX (20.9%) ENX (18.3%) > NFLX (11.91%). These results strongly suggest that adsorption of quinolones by aluminum hydroxide reprecipitated in the small intestine would play an important role in the reduced bioavailability of quinolones after coadministration with aluminum-containing antacids. Levofloxacin (LVFX), (-)-(S)-9-fluoro-2,3-dihydro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid hemihydrate, is a new quinolone antimicrobial agent which exhibits broad-spectrum in vitro bactericidal activities against gram-positive and gramnegative aerobes (8,29). LVFX is the more antibacterially active optical isomer of racemic ofloxacin (OFLX) (8).The bioavailability of quinolone antimicrobial agents including LVFX has been shown to be less when they are ingested with antacids or mineral preparations (13,24), and the binding of metal ions contained in these preparations to the 4-keto-and 3-carboxyl-groups of quinolones to form nonabsorbable chelates has been suggested as the possible mechanism responsible for the reduced absorption of quinolones (4,10,17,19,25). However, attempts to relate the magnitude of reduction in bioavailability by antacids to chemical structures of quinolones or to chelate formation constants have been generally unsuccessful, and the mechanism remains to be elucidated.For the present paper, we studied the mechanisms of pharmacokinetic interaction of LVFX with aluminum hydroxide. The influence of metal ions on the partition coefficient of LVFX between chloroform and phosphate buffer and the adsorptive characteristics of various quinolones such as LVFX, OFLX, enoxacin (ENX), and norfloxacin (NFLX) on the surface ...

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Section: Discussionmentioning

confidence: 86%

Mechanistic study of inhibition of levofloxacin absorption by aluminum hydroxide

Tanaka¹,

Kurata²,

Fujisawa³

et al. 1993

Antimicrob Agents Chemother

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“…The uptake was also unaffected by polycyclic molecules, such as verapamil or paraquat. Yamagushi et al 7 have reported that sparfloxacin absorption across the intestinal epithelium of the rat was inhibited by di-and tripeptides as well as by the -lactam cyclacillin and therefore have suggested the involvement of the H + -peptide cotransport system. Our results do not support this hypothesis.…”

Section: Discussionmentioning

confidence: 99%

Evidence for a Passive Diffusion Mechanism for Sparfloxacin Uptake at the Brush-Border Membrane of the Human Intestinal Cell-linec Caco-2

Cormet

Huneau

Bouras

et al. 1997

Journal of Pharmaceutical Sciences

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The oral uptake of the new fluoroquinolone sparfloxacin was evaluated in the human epithelial cell line Caco-2 that possesses intestinal enterocyte-like properties when cultured in vitro. The uptake of [14C]-sparfloxacin across the apical membrane of Caco-2 cell monolayers was rapid and similar at 25 and 37 degrees C. The initial rate of sparfloxacin uptake was not saturable in the 1-200 microM range and was unaffected by metabolic inhibitors (depletion of ATP store or ouabain), indicating that uptake was energy-independent. The absence of competition with other fluoroquinolones or aminocephalosporins showed that the absorption of sparfloxacin did not involved the H+-coupled dipeptide transport system. Our findings suggest that the apical uptake of sparfloxacin by Caco-2 cells mainly involves diffusion, a finding that is in agreement with the high lipophilicity of sparfloxacin. The intracellular-to-extracellular concentration ratio of approximately 14 after 60 min of incubation suggests the existence of important binding of sparfloxacin to cell components.

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“…The absorption of sparfloxacin has been characterised in rats (Yamaguchi et al 1991b). Sparfloxacin was well absorbed from the duodenum, jejunum, ileum and colon, but not from the stomach.…”

Section: Absorptionmentioning

confidence: 99%

Clinical Pharmacokinetics of Sparfloxacin

Shimada

Nogita

Ishibashi

1993

Clinical Pharmacokinetics

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Sparfloxacin is a recently developed fluoroquinolone. The drug has shown potent antimicrobial activity against a wide range of Gram-positive and Gram-negative bacteria, glucose non-fermenters, anaerobes, Legionella spp., Mycoplasma spp., Chlamydia spp. and Mycobacterium spp. Methicillin-resistant Staphylococcus aureus is also susceptible to sparfloxacin. Plasma sparfloxacin concentrations reach a peak (Cmax) of approximately 0.7 mg/L at 3 to 5 hours after a 200mg oral dose. This is followed by a monophasic slow decrease, with an elimination half-life (t1/2) of 15 to 20 hours. The Cmax and area under the plasma concentration-time curve show dose-related increases. Food intake does not affect the absorption and pharmacokinetics of sparfloxacin. Sparfloxacin binds weakly to plasma protein (37%), and exhibits excellent tissue distribution and effective penetration into extracellular fluids. Concentrations of the drug in most tissues are similar to, or higher than, concomitant plasma concentrations. Sparfloxacin distributes slightly into cerebrospinal fluid. The drug is metabolised to a glucuronide. The urinary excretion of the unchanged drug accounts for 10 to 14% of the given dose. The ratio of Cmax values after multiple and single oral doses is 1.3 to 1.4, but other pharmacokinetic parameters of sparfloxacin are not influenced by multiple doses. Even in patients with severe renal failure, no significant prolongation of the half-life is observed after oral administration. Sparfloxacin appears unlikely to affect the pharmacokinetics of theophylline. Antacids containing aluminium hydroxide reduce the oral bioavailability of sparfloxacin by 25 to 35%. Probenecid does not affect sparfloxacin pharmacokinetics. The pharmacokinetic properties of sparfloxacin allow once-daily administration in the treatment of various infections.

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Intestinal Absorption Characteristics of Sparfloxacin.

Cited by 10 publications

References 5 publications

Mechanistic study of inhibition of levofloxacin absorption by aluminum hydroxide

Mechanistic study of inhibition of levofloxacin absorption by aluminum hydroxide

Evidence for a Passive Diffusion Mechanism for Sparfloxacin Uptake at the Brush-Border Membrane of the Human Intestinal Cell-linec Caco-2

Clinical Pharmacokinetics of Sparfloxacin

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