Transintestinal secretion of ciprofloxacin, grepafloxacin and sparfloxacin: in vitro and in situ inhibition studies.

The influence of the secretion process on the absorption of ciprofloxacin, grepafloxacin and sparfloxacin has been evaluated by means of inhibition studies. Two well known P-glycoprotein inhibitors (cyclosporine, verapamil), a mixed inhibitor of P-glycoprotein and the organic cation transporter OCT1 (quinidine) and a well established MRP substrate (p-aminohipuric acid) have been selected in order to distinguish the possible carriers implicated. An in situ rat gut perfusion model and CACO-2 permeability studies are used. Both methods suggest the involvement of several types of efflux transporters for every fluoroquinolone. The relevance of the secretory pathway depends on the intrinsic permeability of the quinolone. The in vitro model seems to be more suitable for discriminating mechanisms underlying the absorption process, while in situ studies are less sensitive to inhibition studies.

Influencia de fármacos inhibidores de bombas de iones en la acumulación de ofloxacino y grepafloxacino en el interior de los leucocitos polimorfonucleares humanos / Influence of ion pump-inhibiting drugs on the accumulation of ofloxacin and grepafloxacin in human polymorphonuclear leukocytes

En este estudio se ha comprobado la influencia de tres fármacos inhibidores de diferentes bombas de iones (digoxina, omeprazol y verapamilo) sobre la acumulación de ofloxacino y grepafloxacino en el interior de los leucocitos polimorfonucleares humanos. Se establecieron dos condiciones de ensayo: preincubando las células con el fármaco antes de añadir la quinolona, y añadiendo simultáneamente ambos fármacos al medio. El I/E máximo de ofloxacino es diferente según la condición de ensayo: 7,69ñ0,88, 5,64ñ1,91 y 3,56ñ1,04 para el ensayo sin preincubación y preincubando las células durante 30 y 60 minutos a 37 ºC, respectivamente. De igual forma, los máximos para grepafloxacino fueron 61,27ñ3,04, 32,18ñ3,25 y 22,52ñ3,86. La digoxina no modifica significativamente la acumulación de las quinolonas en el interior de los PMN, aunque induce un aumento de los I/E respecto al control. El omeprazol reduce, en general, la acumulación de ambas quinolonas. Con ofloxacino se reducen significativamente los I/E cuando ambos fármacos se añaden simultáneamente al medio; sin embargo, con grepafloxacino es necesaria una incubación previa de 60 minutos para obtener diferencias. El verapamilo produce un aumento significativo del I/E de ambas quinolonas cuando las células se preincuban con dicho fármaco a 10 veces la concentración plasmática. (AU)

[Influence of ion pump-inhibiting drugs on the accumulation of ofloxacin and grepafloxacin in human polymorphonuclear leukocytes]. / Influencia de fármacos inhibidores de bombas de iones en la acumulación de ofloxacino y grepafloxacino en el interior de los leucocitos polimorfonucleares humanos.

In this study we tested the influence of three ion pump-inhibiting drugs (digoxin, omeprazole and verapamil) on the accumulation of ofloxacin and grepafloxacin in human polymorphonuclear leukocytes. Two assay conditions were established: cell preincubation with the drug for 30 or 60 minutes before addition of quinolone, or addition of both drugs simultaneously. The maximum I/E for ofloxacin is different depending on the assay conditions: 7.69+/-0.88; 5.64+/-1.91 and 3.56+/-1.04 for the assay without preincubation and with preincubation for 30 or 60 minutes at 37 masculine C, respectively. Similarly, grepafloxacin reached the following maximums: 61.27+/-3.04; 32.18+/-3.25 and 22.52+/-3.86. Digoxin did not significantly modify the accumulation of the quinolones, but it increased the I/E compared with the control. In general, omeprazole reduced the accumulation of both quinolones. When omeprazole and ofloxacin were added together, ofloxacin's I/E was significantly lower; however, for grepafloxacin, 60 minutes of preincubation were necessary. Verapamil induced a significant increase in the I/E for both quinolones when the cells were preincubated at 10 times the plasma concentration.

[Effect of antiinflammatory agents on the accumulation of ofloxacin in human polymorphonuclear leukocytes]. / Influencia de los antiinflamatorios en la acumulación de ofloxacino en el interior de los leucocitos polimorfonucleares humanos.

The uptake of quinolones is a recently defined pharmacokinetic parameter which is increasing in importance in clinical practice, especially for immunocompromised patients whose polymorphonuclear leukocytes (PMNLs) have their bactericidal systems impaired, or in infections due to bacteria able to survive in the phagocytes. In both situations, antibiotics able to penetrate and be active in the phagocytes are required. The simultaneous administration of an antibiotic and an antiinflammatory drug is frequent, and previous studies have described interactions between the intracellular activity of the quinolones and the presence of phenylbutazone. We studied the effect of the presence of and the pretreatment (37 C for 30 and 60 min) of human PMNLs with the antiinflammatory drugs betamethasone (1 mg/l), hydrocortisone (1 mg/l), phenylbutazone (10 mg/ml), and acetylsalicylic acid (200 mg/l) on the uptake of ofloxacin (10 mg/l) by the PMNLs using a fluorometric method to measure the intra-PMNL concentration of ofloxacin. The presence of betamethasone did not modify the uptake of ofloxacin by PMNLs. Pretreatment of PMNLs with hydrocortisone, phenylbutazone and acetylsalicylic acid produced a significant decrease in the maximum intracellular concentration/extracellular concentration ratios compared with the maximum reached without pretreatment. These results suggest that hydrocortisone, phenylbutazone and acetylsalicylic acid interfere with the uptake of ofloxacin by PMNLs and increase the efflux of ofloxacin from PMNLs.

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

BACKGROUND: Previous work from our laboratory on the effect, in rats, of chronic ethanol intake on the intestinal absorption of ciprofloxacin analogs suggested an increased polarity of the lipoidal membrane constituents without effects on the aqueous environment. The aim of the present study was to investigate the influence of acute ethanol intake on the absorption of the same series of compounds. METHODS: The effects of in situ ethanol exposure on intestinal absorption were determined in rats fed either a standard liquid diet or a 5% (w/v) ethanol-containing liquid diet. Acute intestinal exposure to 5% (w/v) ethanol was performed in situ in each feeding group. The biophysical absorption model was used to establish correlations between the actual absorption rate constants, and the lipophilicity indexes, for each group of rats. RESULTS: Acute exposure to ethanol produces an increase only in the absorption of hydrophilic homologs in both control and chronic ethanol fed groups. This suggests the absence of homeoviscous adaptation of the intestinal membrane. The biophysical model used allows us to discriminate between the effects of acute and chronic ethanol treatment on the intestinal membrane. CONCLUSIONS: These results suggest that in contrast to previous reports chronic ethanol treatment increases membrane polarity and acute alcohol intake appears to modify membrane fluidity.