Differences in the hepatobiliary transport of two quinolone antibiotics, grepafloxacin and lomefloxacin, in the rat

Sasabe, Hiroyuki; Kato, Yukio; Terasaki, Toshio; Tsuji, Akira; Sugiyama, Yuichi

doi:10.1002/(sici)1099-081x(199904)20:3<151::aid-bdd168>3.0.co;2-p

Cited by 21 publications

(9 citation statements)

References 15 publications

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“…The conclusion that grepafloxacin transport is also mediated by MRP2 is supported by studies carried out in rodent liver. For example, in MRP2‐deficient rats, Sasabe et al . (1998) found that the hepatobiliary clearance of grepafloxacin was reduced by 38%, whereas the excretion of the 3‐glucuronide metabolite via the same route was completely abolished.…”

Section: Discussionmentioning

confidence: 99%

“…(1998) have also suggested that P‐glycoprotein is involved in fluoroquinolone secretion by LLC‐PK 1 (porcine kidney) cells. In addition, the biliary secretion of grepafloxacin in mutant Eisai‐hyperbilirubinaemic rats deficient in MRP2 (multidrug resistance‐associated protein 2, also known as the canalicular multispecific organic anion transporter, cMOAT) was reduced to 38% of values seen in control animals (Sasabe et al ., 1998). Our own recent work has shown that certain bile acids, such as cholic acid, induce toxicity in Caco‐2 epithelial monolayers when they are preferentially presented at high concentrations from the basolateral epithelial surfaces (Lowes & Simmons, 2001).…”

Section: Introductionmentioning

confidence: 99%

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Multiple pathways for fluoroquinolone secretion by human intestinal epithelial (Caco‐2) cells

Lowes

Simmons

2002

British J Pharmacology

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upon Tyne NE2 4HH1 Human intestinal epithelial Caco-2 cells, T84 cells, and MDCKII cells transfected with human MDR1, were used to investigate the mechanistic basis of transintestinal¯uoroquinolone secretion. 2 The¯uoroquinolone grepa¯oxacin was secreted across Caco-2 monolayers by a saturable process (V max =16.9+3.4 nmol.cm 72 .h 71 ). Net secretion was reduced by 2-deoxyglucose/azide treatment to reduce intracellular ATP. 3 Grepa¯oxacin inhibited [ 14 C]-cipro¯oxacin (100 mM) secretion across Caco-2 monolayers (K 0.5 =0.8 mM), and concurrently increased the cellular accumulation of cipro¯oxacin from the basal medium, indicating inhibition of export across the apical membrane. 4 The unconjugated bile acid, cholic acid, was secreted across Caco-2 monolayers, and this secretion was sensitive to inhibition by the MRP-selective inhibitor MK-571, suggesting MRP2 involvement. Secretion of cholic acid (10 mM) across the apical membrane was also inhibited by grepa¯oxacin (K 0.5 =0.3 mM), but not by cipro¯oxacin. 5 In MDCKII-MDR1 monolayers, net secretion of grepa¯oxacin was increased by 3.5 fold compared with untransfected controls. Neither cipro¯oxacin nor cholic acid showed net secretion in either MDCKII or MDCKII-MDR1 monolayers, showing that in contrast to grepa¯oxacin, neither are substrates for MDR1. 6 In T84 monolayers, which express MDR1 but not MRP2, neither cipro¯oxacin nor cholic acid was secreted, whilst the V max for grepa¯oxacin secretion was lower than in Caco-2 cells, which express both MDR1 and MRP2. 7 In conclusion, the transepithelial secretion of grepa¯oxacin is mediated by both MRP2 and MDR1, whereas cipro¯oxacin is a substrate for neither. Grepa¯oxacin also competes for the cipro¯oxacin-sensitive pathway, which remains to be elucidated.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Multiple pathways for fluoroquinolone secretion by human intestinal epithelial (Caco‐2) cells

Lowes

Simmons

2002

British J Pharmacology

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“…Thus, biliary clearance is governed not only by the degree of hepatic uptake but also by the intrinsic ability of excretion into bile across the bile canalicular membrane. A series of in vivo and in vitro experiments have demonstrated the possible involvement of ABC efflux proteins in the biliary excretion of quinolones (Sasabe et al 1997(Sasabe et al , 1998aNiinuma et al 1999;Figure 5. Plasma concentration (a), biliary excretion rate of ATFX (b) and biliary excretion rate of ATFX glucuronide (c) in normal rats () and CCl 4 -EHI 24h rats (.)…”

Section: Discussionmentioning

confidence: 99%

Possible multiple transporters were involved in hepatobiliary excretion of antofloxacin in rats

Liu

Xie

et al. 2007

Xenobiotica

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1. The aim of the current study was to investigate the characteristics of biliary excretion of antofloxacin (ATFX) in rats. Rats received a bolus intravenous injection followed by a constant-rate infusion of ATFX. When plasma concentrations of ATFX reached steady state, cyclosporin A, erythromycin, probenecid, cimetidine and diclofenac were administered intravenously to the rats. Samples of blood and bile were collected and the concentrations of ATFX were measured and the corresponding pharmacokinetic parameters were estimated. 2. Biliary excretion of ATFX was observed in rats subjected to CCl(4)-induced experimental hepatic injury for 24 h (CCl(4)-EHI(24h)). Steady state concentrations of ATFX were attained at 60 min following infusion. 3. A slight increase in concentration of ATFX in plasma was observed after cyclosporin A, erythromycin, probenecid and cimetidine treatment. Significant increases in ATFX plasma levels were found in rats treated with diclofenac. Cyclosporin A, erythromycin, probenecid, cimetidine and diclofenac treatment significantly decreased the steady state biliary clearance of ATFX to 55, 68, 54, 53 and 56% of control values, respectively. 4. Cyclosprin A, probenecid, erythromycin and cimetidine also inhibited the biliary excretion of ATFX glucuronide. Significant decrease in the steady state biliary clearance of ATFX and its glucuronide was observed in CCl(4)-EHI(24h) rats. 5. These results indicate that multiple transporters are possibly involved in the biliary excretion of ATFX.

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“…Such high concentrations might not be reached in the liver, because passive diffusion has been demonstrated for the transport of FQs between systemic circulation and liver in some animal species including humans (Memin et al. , 1996) and rats (Sasabe et al. , 1998).…”

Section: Discussionmentioning

confidence: 99%

Effect of ofloxacin on theophylline pharmacokinetics at clinical dosage in dogs

Regmi

El‐Aty

Kubota

et al. 2006

Vet Pharm & Therapeutics

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We examined the effects of ofloxacin (OFX) and norfloxacin (NFX) on theophylline (TP) pharmacokinetics in dogs. OFX, as a noncompetitive and mechanism-based inhibitor, and NFX, as a noncompetitive inhibitor, were orally administered (5 mg/kg) for a single dose or multiple doses (12 hourly for 3 days). TP (5 mg/kg, i.v) was injected at 2 h after the final dose of the fluoroquinolones (FQs). The same dose of TP was injected (i.v) 3 weeks before the start of FQs treatment for control. Multiple doses of OFX significantly reduced the total body clearance (Cl(B)) of TP from 0.117 to 0.085 L/h/kg, although a single dose did not change it. Neither a single dose nor multiple doses of NFX changed the TP pharmacokinetics. Plasma NFX concentrations increased after multiple doses. Those of OFX also increased but were still two orders of magnitude below the K(i) for noncompetitive inhibition of CYP1A in dogs. Time-dependent reduction in Cl(B) of TP suggests that mechanism-based inhibition of OFX was the major mode to decrease Cl(B) of TP. The mechanism-based inhibition may result in substantial inhibition of CYP1A activities in clinical conditions.

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Differences in the hepatobiliary transport of two quinolone antibiotics, grepafloxacin and lomefloxacin, in the rat

Cited by 21 publications

References 15 publications

Multiple pathways for fluoroquinolone secretion by human intestinal epithelial (Caco‐2) cells

Multiple pathways for fluoroquinolone secretion by human intestinal epithelial (Caco‐2) cells

Possible multiple transporters were involved in hepatobiliary excretion of antofloxacin in rats

Effect of ofloxacin on theophylline pharmacokinetics at clinical dosage in dogs

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