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 ...

The studies on the mechanism of pharmacokinetic interaction of aluminum hydroxide with new quinolones, ofloxacin, enoxacin and norfloxacin, were performed in rats. New quinolones (20 mg/kg) were administered orally with or without aluminum hydroxide or aluminum chloride (50 mg/kg). Co-administration of alumi num hydroxide induced a significant decrease in C.ax of enoxacin and norfloxacin , and in the AUC values of the three drugs. This effect was enhanced by co-admini stration of aluminum chloride. The combination of aluminum hydroxide caused a significant increase in the intestinal contents and decrease in urinary excretion of new quinolones. The formation of the stable chelate of new quinolones with All+ ions formed from aluminum hydroxide in the same acidic solution as gastric juice was observed. Thus, it is concluded that the co-administration of aluminum hydro xide affects the pharmacokinetics of new quinolones, probably, by the inhibition of the intestinal absorption of new quinolones by the chelate formation of these compounds with All+ ions released from aluminum hydroxide in the gastric juice.

1. Stereoselective metabolic disposition of ofloxacin (OFLX) was studied in rats after oral administration of S-(-)-14C-OFLX and R-(+)-14C-OFLX at a dose of 20 mg/kg. 2. Radioactivity of the S-(-)-isomer was eliminated from blood much faster than that of the R-(+)-isomer. Marked differences in pharmacokinetic parameters exist between the enantiomers; the half life and AUC values of R-(+)-OFLX were greater than those of S-(-)-OFLX. Enantiomeric differences were also seen in the excretion of radioactivity, especially in biliary excretion. 3. 31.3 and 7.4% dose were excreted in the 8 h bile as ester glucuronides after oral administration of S-(-)- and R-(+)-OFLX, respectively. The enantiomeric difference in biliary excretion may be caused by stereoselective glucuronidation of S-(-)-OFLX to the ester glucuronide. 4. The metabolite pattern in serum and urine showed that the ester glucuronide of S-(-)-OFLX was more predominant than that of R-(+)-OFLX. 5. The stereoselective ester glucuronidation of the S-(-)-isomer in rats may induce significant differences in the pharmacokinetic parameters of S-(-)- and R-(+)-OFLX.

Effects of repeated oral administration of new quinolones, ofloxacin, enoxacin and norfloxacin, once daily for 7 days, on the drug-metabolizing enzyme system of rat hepatic microsomes were studied in comparison with that of phenobarbital, a potent inducer of cytochromes P-450. Treatment of phenobarbital at the oral dose of 120 mg/kg induced significant increases in the contents of cytochrome P-450, cytochrome b₅ and NADPH-cytochrome P-450 reductase and in the activity of ethoxycou-marin O-deethylase, and significant decreases in the activities of benzphetamine N-de-methylase and aniline hydroxylase. However, ofloxacin, enoxacin and norfloxacin at the oral dose levels of 80 and 320 mg/kg showed no significant effect on the content of each constituent of the drug-metabolizing enzyme system, and the three enzyme activities. Thus, it is concluded that new quinolones including ofloxacin have no ability to induce a cytochrome-P-450-dependent monooxygenase system.

1. The stereoselective disposition of ofloxacin (OFLX) was studied in rats, dogs and monkeys after oral administration of racemic OFLX. 2. In rats serum concentrations of (R)-(+)-OFLX were much greater than those of (S)-(-)-OFLX, which is the active form of OFLX. In monkeys, by contrast, serum concentrations of (S)-(-)-OFLX predominated over (R)-(+)-OFLX levels. In dogs there were no differences in AUC or Cmax between the enantiomers. Thus, there exists a species-related difference in the stereoselective disposition of OFLX. 3. In rats the stereoselective differences were mainly due to stereoselective glucuronidation; OFLX is hardly metabolized in dogs, monkeys and humans. 4. In monkeys the AUC of (S)-(-)-OFLX was increased by co-administration of the (R)-(+)-form, indicating that the stereoselectivity of OFLX disposition in monkeys may be caused by competition between the enantiomers for renal excretion, especially for renal tubular secretion.