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Kenichi Inui - One of the best experts on this subject based on the ideXlab platform.
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Inui K. Pharmacokinetic role of P-glycoprotein in oral bioavailability and intestinal secretion of Grepafloxacin in vivo
2016Co-Authors: Hiroaki Yamaguchi, Hideyuki Saito, Ikuko Yano, Kenichi InuiAbstract:The purpose of this study was to clarify the contribution of P-glycoprotein to the bioavailability and intestinal secretion of Grepafloxacin and levofloxacin in vivo. Plasma concentrations of Grepafloxacin and levofloxacin after intravenous and intraint-estinal administration were increased by cyclosporin A, a P-glycoprotein inhibitor, in rats. The total body clearance and volume of distribution at steady state of Grepafloxacin were significantly decreased to 60 and 63 % of the corresponding control values by cyclosporin A. The apparent oral clearance of Grepafloxacin was decreased to 33 % of the control, and the bioavailability of Grepafloxacin was increased to 95 % by cyclo-sporin A from 53 % in the controls. Intestinal clearance of Grepafloxacin and levofloxacin were decreased to one-half and one-third of the control, respectively, and biliary clearance o
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Secretory mechanisms of Grepafloxacin and levofloxacin in the human intestinal cell line caco-2
2016Co-Authors: Hiroaki Yamaguchi, Ikuko Yano, Yukiya Hashimoto, Kenichi InuiAbstract:Grepafloxacin and levofloxacin transport by Caco-2 cell mono-layers was examined to characterize the intestinal behavior of these quinolones. The levels of transcellular transport of [14C]Grepafloxacin and [14C]levofloxacin from the basolateral to the apical side were greater than those in the opposite direc-tion. The unidirectional transport was inhibited by the presence of excess unlabeled quinolones, accompanied by increased accumulation. The inhibitory effects of cyclosporin A plus Grepafloxacin on basolateral-to-apical transcellular transport and cellular accumulation of [14C]Grepafloxacin were compara-ble to those of cyclosporin A alone, indicating that the transport of Grepafloxacin across the apical membrane was mainly me-diated by P-glycoprotein. On the other hand, basolateral-to-apical transcellular transport of [14C]levofloxacin in the pres
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Transport characteristics of Grepafloxacin and levofloxacin in the human intestinal cell line Caco-2.
European journal of pharmacology, 2001Co-Authors: Hiroaki Yamaguchi, Hideyuki Saito, Ikuko Yano, Kenichi InuiAbstract:Transport characteristics of Grepafloxacin and levofloxacin across the apical membrane of Caco-2 cells were examined. Both Grepafloxacin and levofloxacin uptakes increased rapidly, and were temperature-dependent. Grepafloxacin and levofloxacin uptakes showed concentration-dependent saturation with Michaelis constants of 3.9 and 9.3 mM, respectively. Uptake of Grepafloxacin and levofloxacin increased in Cl(-)-free and ATP depleted conditions, suggesting the involvement of an efflux transport system different from the uptake mechanism. However, cyclosporin A, a typical inhibitor of P-glycoprotein, did not affect the uptake of these drugs. Unlabeled Grepafloxacin, unlabeled levofloxacin and quinidine inhibited the uptake of Grepafloxacin and levofloxacin under Cl(-)-free conditions. Tetraethylammonium, cimetidine, p-aminohippurate, probenecid, amino acids, beta-lactam antibiotic or monocarboxylates did not inhibit the uptake of Grepafloxacin and levofloxacin under the same conditions. In conclusion, our results suggested that Grepafloxacin and levofloxacin uptakes were mediated by a specific transport system distinct from those for organic cations and anions, amino acids, dipeptides and monocarboxylates.
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Secretory mechanisms of Grepafloxacin and levofloxacin in the human intestinal cell line caco-2.
Journal of Pharmacology and Experimental Therapeutics, 2000Co-Authors: Hiroaki Yamaguchi, Ikuko Yano, Yukiya Hashimoto, Kenichi InuiAbstract:Grepafloxacin and levofloxacin transport by Caco-2 cell monolayers was examined to characterize the intestinal behavior of these quinolones. The levels of transcellular transport of [14C]Grepafloxacin and [14C]levofloxacin from the basolateral to the apical side were greater than those in the opposite direction. The unidirectional transport was inhibited by the presence of excess unlabeled quinolones, accompanied by increased accumulation. The inhibitory effects of cyclosporin A plus Grepafloxacin on basolateral-to-apical transcellular transport and cellular accumulation of [14C]Grepafloxacin were comparable to those of cyclosporin A alone, indicating that the transport of Grepafloxacin across the apical membrane was mainly mediated by P-glycoprotein. On the other hand, basolateral-to-apical transcellular transport of [14C]levofloxacin in the presence of cyclosporin A was decreased by unlabeled levofloxacin, Grepafloxacin, and enoxacin, accompanied by significantly increased cellular accumulation. The organic cation cimetidine, organic anion p -aminohippurate, and the multidrug resistance-related protein (MRP) modulator probenecid did not affect the transcellular transport of [14C]Grepafloxacin or [14C]levofloxacin in the presence of cyclosporin A. The basolateral-to-apical transcellular transport of levofloxacin in the presence of cyclosporin A showed concentration-dependent saturation with an apparent Michaelis constant of 5.6 mM. In conclusion, these results suggested that basolateral-to-apical flux of quinolones was mediated by P-glycoprotein and a specific transport system distinct from organic cation and anion transporters and MRP.
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distribution characteristics of levofloxacin and Grepafloxacin in rat kidney
Pharmaceutical Research, 1999Co-Authors: Tatsuya Ito, Ikuko Yano, Yukiya Hashimoto, Satohiro Masuda, Kenichi InuiAbstract:Purpose. To elucidate the renal distribution of quinolones, we examined the uptake of levofloxacin and Grepafloxacin in vivo and in rat renal cortical slices.
Hiroaki Yamaguchi - One of the best experts on this subject based on the ideXlab platform.
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Inui K. Pharmacokinetic role of P-glycoprotein in oral bioavailability and intestinal secretion of Grepafloxacin in vivo
2016Co-Authors: Hiroaki Yamaguchi, Hideyuki Saito, Ikuko Yano, Kenichi InuiAbstract:The purpose of this study was to clarify the contribution of P-glycoprotein to the bioavailability and intestinal secretion of Grepafloxacin and levofloxacin in vivo. Plasma concentrations of Grepafloxacin and levofloxacin after intravenous and intraint-estinal administration were increased by cyclosporin A, a P-glycoprotein inhibitor, in rats. The total body clearance and volume of distribution at steady state of Grepafloxacin were significantly decreased to 60 and 63 % of the corresponding control values by cyclosporin A. The apparent oral clearance of Grepafloxacin was decreased to 33 % of the control, and the bioavailability of Grepafloxacin was increased to 95 % by cyclo-sporin A from 53 % in the controls. Intestinal clearance of Grepafloxacin and levofloxacin were decreased to one-half and one-third of the control, respectively, and biliary clearance o
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Secretory mechanisms of Grepafloxacin and levofloxacin in the human intestinal cell line caco-2
2016Co-Authors: Hiroaki Yamaguchi, Ikuko Yano, Yukiya Hashimoto, Kenichi InuiAbstract:Grepafloxacin and levofloxacin transport by Caco-2 cell mono-layers was examined to characterize the intestinal behavior of these quinolones. The levels of transcellular transport of [14C]Grepafloxacin and [14C]levofloxacin from the basolateral to the apical side were greater than those in the opposite direc-tion. The unidirectional transport was inhibited by the presence of excess unlabeled quinolones, accompanied by increased accumulation. The inhibitory effects of cyclosporin A plus Grepafloxacin on basolateral-to-apical transcellular transport and cellular accumulation of [14C]Grepafloxacin were compara-ble to those of cyclosporin A alone, indicating that the transport of Grepafloxacin across the apical membrane was mainly me-diated by P-glycoprotein. On the other hand, basolateral-to-apical transcellular transport of [14C]levofloxacin in the pres
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Pharmacokinetic Role of P-Glycoprotein in Oral Bioavailability and Intestinal Secretion of Grepafloxacin in Vivo
Journal of Pharmacology and Experimental Therapeutics, 2002Co-Authors: Hiroaki Yamaguchi, Ikuko Yano, Hideyuki SaitoAbstract:The purpose of this study was to clarify the contribution of P-glycoprotein to the bioavailability and intestinal secretion of Grepafloxacin and levofloxacin in vivo. Plasma concentrations of Grepafloxacin and levofloxacin after intravenous and intraintestinal administration were increased by cyclosporin A, a P-glycoprotein inhibitor, in rats. The total body clearance and volume of distribution at steady state of Grepafloxacin were significantly decreased to 60 and 63% of the corresponding control values by cyclosporin A. The apparent oral clearance of Grepafloxacin was decreased to 33% of the control, and the bioavailability of Grepafloxacin was increased to 95% by cyclosporin A from 53% in the controls. Intestinal clearance of Grepafloxacin and levofloxacin were decreased to one-half and one-third of the control, respectively, and biliary clearance of Grepafloxacin was also decreased to one-third with cyclosporin A in rats. Intestinal secretion of Grepafloxacin in mdr1a/1b (−/−) mice, which lack mdr1 -type P-glycoproteins, was significantly decreased compared with wild-type mice, although the biliary secretion was similar. Intestinal secretion of Grepafloxacin in wild-type mice treated with cyclosporin A was comparable to those in mdr1a/1b (−/−) mice with or without cyclosporin A, indicating that cyclosporin A completely inhibited P-glycoprotein-mediated intestinal transport of Grepafloxacin. In conclusion, our results indicated that P-glycoprotein mediated the intestinal secretion of Grepafloxacin and limited the bioavailability of this drug in vivo.
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Transport characteristics of Grepafloxacin and levofloxacin in the human intestinal cell line Caco-2.
European journal of pharmacology, 2001Co-Authors: Hiroaki Yamaguchi, Hideyuki Saito, Ikuko Yano, Kenichi InuiAbstract:Transport characteristics of Grepafloxacin and levofloxacin across the apical membrane of Caco-2 cells were examined. Both Grepafloxacin and levofloxacin uptakes increased rapidly, and were temperature-dependent. Grepafloxacin and levofloxacin uptakes showed concentration-dependent saturation with Michaelis constants of 3.9 and 9.3 mM, respectively. Uptake of Grepafloxacin and levofloxacin increased in Cl(-)-free and ATP depleted conditions, suggesting the involvement of an efflux transport system different from the uptake mechanism. However, cyclosporin A, a typical inhibitor of P-glycoprotein, did not affect the uptake of these drugs. Unlabeled Grepafloxacin, unlabeled levofloxacin and quinidine inhibited the uptake of Grepafloxacin and levofloxacin under Cl(-)-free conditions. Tetraethylammonium, cimetidine, p-aminohippurate, probenecid, amino acids, beta-lactam antibiotic or monocarboxylates did not inhibit the uptake of Grepafloxacin and levofloxacin under the same conditions. In conclusion, our results suggested that Grepafloxacin and levofloxacin uptakes were mediated by a specific transport system distinct from those for organic cations and anions, amino acids, dipeptides and monocarboxylates.
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Secretory mechanisms of Grepafloxacin and levofloxacin in the human intestinal cell line caco-2.
Journal of Pharmacology and Experimental Therapeutics, 2000Co-Authors: Hiroaki Yamaguchi, Ikuko Yano, Yukiya Hashimoto, Kenichi InuiAbstract:Grepafloxacin and levofloxacin transport by Caco-2 cell monolayers was examined to characterize the intestinal behavior of these quinolones. The levels of transcellular transport of [14C]Grepafloxacin and [14C]levofloxacin from the basolateral to the apical side were greater than those in the opposite direction. The unidirectional transport was inhibited by the presence of excess unlabeled quinolones, accompanied by increased accumulation. The inhibitory effects of cyclosporin A plus Grepafloxacin on basolateral-to-apical transcellular transport and cellular accumulation of [14C]Grepafloxacin were comparable to those of cyclosporin A alone, indicating that the transport of Grepafloxacin across the apical membrane was mainly mediated by P-glycoprotein. On the other hand, basolateral-to-apical transcellular transport of [14C]levofloxacin in the presence of cyclosporin A was decreased by unlabeled levofloxacin, Grepafloxacin, and enoxacin, accompanied by significantly increased cellular accumulation. The organic cation cimetidine, organic anion p -aminohippurate, and the multidrug resistance-related protein (MRP) modulator probenecid did not affect the transcellular transport of [14C]Grepafloxacin or [14C]levofloxacin in the presence of cyclosporin A. The basolateral-to-apical transcellular transport of levofloxacin in the presence of cyclosporin A showed concentration-dependent saturation with an apparent Michaelis constant of 5.6 mM. In conclusion, these results suggested that basolateral-to-apical flux of quinolones was mediated by P-glycoprotein and a specific transport system distinct from organic cation and anion transporters and MRP.
Ikuko Yano - One of the best experts on this subject based on the ideXlab platform.
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Inui K. Pharmacokinetic role of P-glycoprotein in oral bioavailability and intestinal secretion of Grepafloxacin in vivo
2016Co-Authors: Hiroaki Yamaguchi, Hideyuki Saito, Ikuko Yano, Kenichi InuiAbstract:The purpose of this study was to clarify the contribution of P-glycoprotein to the bioavailability and intestinal secretion of Grepafloxacin and levofloxacin in vivo. Plasma concentrations of Grepafloxacin and levofloxacin after intravenous and intraint-estinal administration were increased by cyclosporin A, a P-glycoprotein inhibitor, in rats. The total body clearance and volume of distribution at steady state of Grepafloxacin were significantly decreased to 60 and 63 % of the corresponding control values by cyclosporin A. The apparent oral clearance of Grepafloxacin was decreased to 33 % of the control, and the bioavailability of Grepafloxacin was increased to 95 % by cyclo-sporin A from 53 % in the controls. Intestinal clearance of Grepafloxacin and levofloxacin were decreased to one-half and one-third of the control, respectively, and biliary clearance o
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Secretory mechanisms of Grepafloxacin and levofloxacin in the human intestinal cell line caco-2
2016Co-Authors: Hiroaki Yamaguchi, Ikuko Yano, Yukiya Hashimoto, Kenichi InuiAbstract:Grepafloxacin and levofloxacin transport by Caco-2 cell mono-layers was examined to characterize the intestinal behavior of these quinolones. The levels of transcellular transport of [14C]Grepafloxacin and [14C]levofloxacin from the basolateral to the apical side were greater than those in the opposite direc-tion. The unidirectional transport was inhibited by the presence of excess unlabeled quinolones, accompanied by increased accumulation. The inhibitory effects of cyclosporin A plus Grepafloxacin on basolateral-to-apical transcellular transport and cellular accumulation of [14C]Grepafloxacin were compara-ble to those of cyclosporin A alone, indicating that the transport of Grepafloxacin across the apical membrane was mainly me-diated by P-glycoprotein. On the other hand, basolateral-to-apical transcellular transport of [14C]levofloxacin in the pres
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Pharmacokinetic Role of P-Glycoprotein in Oral Bioavailability and Intestinal Secretion of Grepafloxacin in Vivo
Journal of Pharmacology and Experimental Therapeutics, 2002Co-Authors: Hiroaki Yamaguchi, Ikuko Yano, Hideyuki SaitoAbstract:The purpose of this study was to clarify the contribution of P-glycoprotein to the bioavailability and intestinal secretion of Grepafloxacin and levofloxacin in vivo. Plasma concentrations of Grepafloxacin and levofloxacin after intravenous and intraintestinal administration were increased by cyclosporin A, a P-glycoprotein inhibitor, in rats. The total body clearance and volume of distribution at steady state of Grepafloxacin were significantly decreased to 60 and 63% of the corresponding control values by cyclosporin A. The apparent oral clearance of Grepafloxacin was decreased to 33% of the control, and the bioavailability of Grepafloxacin was increased to 95% by cyclosporin A from 53% in the controls. Intestinal clearance of Grepafloxacin and levofloxacin were decreased to one-half and one-third of the control, respectively, and biliary clearance of Grepafloxacin was also decreased to one-third with cyclosporin A in rats. Intestinal secretion of Grepafloxacin in mdr1a/1b (−/−) mice, which lack mdr1 -type P-glycoproteins, was significantly decreased compared with wild-type mice, although the biliary secretion was similar. Intestinal secretion of Grepafloxacin in wild-type mice treated with cyclosporin A was comparable to those in mdr1a/1b (−/−) mice with or without cyclosporin A, indicating that cyclosporin A completely inhibited P-glycoprotein-mediated intestinal transport of Grepafloxacin. In conclusion, our results indicated that P-glycoprotein mediated the intestinal secretion of Grepafloxacin and limited the bioavailability of this drug in vivo.
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Transport characteristics of Grepafloxacin and levofloxacin in the human intestinal cell line Caco-2.
European journal of pharmacology, 2001Co-Authors: Hiroaki Yamaguchi, Hideyuki Saito, Ikuko Yano, Kenichi InuiAbstract:Transport characteristics of Grepafloxacin and levofloxacin across the apical membrane of Caco-2 cells were examined. Both Grepafloxacin and levofloxacin uptakes increased rapidly, and were temperature-dependent. Grepafloxacin and levofloxacin uptakes showed concentration-dependent saturation with Michaelis constants of 3.9 and 9.3 mM, respectively. Uptake of Grepafloxacin and levofloxacin increased in Cl(-)-free and ATP depleted conditions, suggesting the involvement of an efflux transport system different from the uptake mechanism. However, cyclosporin A, a typical inhibitor of P-glycoprotein, did not affect the uptake of these drugs. Unlabeled Grepafloxacin, unlabeled levofloxacin and quinidine inhibited the uptake of Grepafloxacin and levofloxacin under Cl(-)-free conditions. Tetraethylammonium, cimetidine, p-aminohippurate, probenecid, amino acids, beta-lactam antibiotic or monocarboxylates did not inhibit the uptake of Grepafloxacin and levofloxacin under the same conditions. In conclusion, our results suggested that Grepafloxacin and levofloxacin uptakes were mediated by a specific transport system distinct from those for organic cations and anions, amino acids, dipeptides and monocarboxylates.
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Secretory mechanisms of Grepafloxacin and levofloxacin in the human intestinal cell line caco-2.
Journal of Pharmacology and Experimental Therapeutics, 2000Co-Authors: Hiroaki Yamaguchi, Ikuko Yano, Yukiya Hashimoto, Kenichi InuiAbstract:Grepafloxacin and levofloxacin transport by Caco-2 cell monolayers was examined to characterize the intestinal behavior of these quinolones. The levels of transcellular transport of [14C]Grepafloxacin and [14C]levofloxacin from the basolateral to the apical side were greater than those in the opposite direction. The unidirectional transport was inhibited by the presence of excess unlabeled quinolones, accompanied by increased accumulation. The inhibitory effects of cyclosporin A plus Grepafloxacin on basolateral-to-apical transcellular transport and cellular accumulation of [14C]Grepafloxacin were comparable to those of cyclosporin A alone, indicating that the transport of Grepafloxacin across the apical membrane was mainly mediated by P-glycoprotein. On the other hand, basolateral-to-apical transcellular transport of [14C]levofloxacin in the presence of cyclosporin A was decreased by unlabeled levofloxacin, Grepafloxacin, and enoxacin, accompanied by significantly increased cellular accumulation. The organic cation cimetidine, organic anion p -aminohippurate, and the multidrug resistance-related protein (MRP) modulator probenecid did not affect the transcellular transport of [14C]Grepafloxacin or [14C]levofloxacin in the presence of cyclosporin A. The basolateral-to-apical transcellular transport of levofloxacin in the presence of cyclosporin A showed concentration-dependent saturation with an apparent Michaelis constant of 5.6 mM. In conclusion, these results suggested that basolateral-to-apical flux of quinolones was mediated by P-glycoprotein and a specific transport system distinct from organic cation and anion transporters and MRP.
A Maroli - One of the best experts on this subject based on the ideXlab platform.
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randomized double blind comparative study of Grepafloxacin and amoxycillin in the treatment of patients with community acquired pneumonia
Journal of Antimicrobial Chemotherapy, 1997Co-Authors: B Odoherty, Ross Pettit, D A Dutchman, A MaroliAbstract:This randomized, multicentre, double-blind, double-dummy study assessed the efficacy and safety of 7 or 10 day regimens of Grepafloxacin, 600 mg od, compared with amoxycillin, 500 mg tds, in the treatment of community-acquired pneumonia (CAP). A total of 264 patients were recruited at 43 centres (127 received Grepafloxacin and 137 received amoxycillin), of whom 207 patients (78%) completed the study. Clinical and microbiological efficacy were assessed at the end-of-treatment visit (3-5 days after the last dose) and at the follow-up visit (28-42 days after the last dose). At follow-up, patients in the evaluable population treated with Grepafloxacin demonstrated a clinical response rate (76%; 87/114) equivalent to that seen with amoxycillin (74%, 85/111, 95% Cl = -12%, 10%) while, in the intent-to-treat population with a documented bacterial pathogen, the clinical success rate in the Grepafloxacin group (78%, 29/37) was significantly higher than in the amoxycillin group (58%, 28/48), 95% Cl = 2%, 43%). In patients from the evaluable population in whom the pathogens were documented the clinical success rate favoured Grepafloxacin, compared with amoxycillin (79%, 26/33 versus 63%, 26/42, respectively; 95% Cl = -5.2%, 38.1%). Microbiological eradication with Grepafloxacin was statistically superior to amoxycillin in the evaluable population; the success rate was 89% (32/36) in the Grepafloxacin group compared with 71% (32/45) for the amoxycillin group (95% Cl = 2%, 37%). The pathogens most commonly isolated from patients were Haemophilus Influenzae, Moraxella catarrhalis and Streptococcus pneumoniae. The success rates for infections caused by S. pneumoniae and H. influenzae at follow-up were higher with Grepafloxacin than with amoxycillin. Grepafloxacin was well tolerated, with a safety profile comparable to that of amoxycillin. The therapeutic judgement of patients and investigators at the patient's last visit, as well as the assessment of individual respiratory signs and symptoms, yielded comparable results with both treatments. The results of this study indicate that Grepafloxacin, 600 mg od for 7-10 days, is equivalent to or better than amoxycillin, 500 mg tds for 7-10 days in achieving a successful clinical and microbiological response in the treatment of patients with CAP.
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efficacy and safety of Grepafloxacin 600 mg daily for 10 days in patients with community acquired pneumonia
Clinical Therapeutics, 1997Co-Authors: Stuart Topkis, Herbert Swarz, Sally A Breisch, A MaroliAbstract:The efficacy and safety of Grepafloxacin in treating patients with community-acquired pneumonia (CAP) was assessed in an open-label, noncomparative study. Patients (N = 273) received Grepafloxacin 600 mg QD for 10 days. A total of 237 patients (87%) completed the study. In assessable patients, the clinical success rate at follow-up (4 to 6 weeks after the last dose) was 89% (211/238 patients). In microbiologically assessable patients, the eradication rate at follow-up was 95% (86/91 isolates). Grepafloxacin was highly effective in the treatment of bacterial CAP caused by Streptococcus pneumoniae (irrespective of penicillin susceptibility), Haemophilus influenzae, Haemophilus parainfluenzae, Moraxella catarrhalis, and Staphylococcus aureus and in the therapy of atypical pneumonia caused by Mycoplasma pneumoniae and Legionella pneumophila. Grepafloxacin was well tolerated, with the most frequently reported drug-related adverse events being taste perversion and nausea. Grepafloxacin 600 mg QD for 10 days was highly effective and well tolerated in the treatment of patients with CAP.
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comparison of single dose oral Grepafloxacin with cefixime for treatment of uncomplicated gonorrhea in men the std study group
Antimicrobial Agents and Chemotherapy, 1997Co-Authors: Edward W Hook, Robert B Jones, William M Mccormack, David H Martin, Karen Bean, A MaroliAbstract:In a randomized open study, 351 male patients with uncomplicated gonorrhea were given single oral doses of Grepafloxacin (400 mg) or cefixime (400 mg). In the 299 microbiologically evaluable patients, urethral infections were cured in 99% (147 of 149) of those receiving Grepafloxacin and 97% (145 of 150) of those given cefixime. Eradication rates for both regimens were 100% in the 16% (47 of 299) of participants who were infected with penicillin-resistant Neisseria gonorrhoeae and 97% in the 21% (62 of 299) of participants infected with tetracycline-resistant strains. Grepafloxacin is a well-tolerated alternative to cefixime for treatment of uncomplicated gonorrhea in males.
Hideyuki Saito - One of the best experts on this subject based on the ideXlab platform.
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Inui K. Pharmacokinetic role of P-glycoprotein in oral bioavailability and intestinal secretion of Grepafloxacin in vivo
2016Co-Authors: Hiroaki Yamaguchi, Hideyuki Saito, Ikuko Yano, Kenichi InuiAbstract:The purpose of this study was to clarify the contribution of P-glycoprotein to the bioavailability and intestinal secretion of Grepafloxacin and levofloxacin in vivo. Plasma concentrations of Grepafloxacin and levofloxacin after intravenous and intraint-estinal administration were increased by cyclosporin A, a P-glycoprotein inhibitor, in rats. The total body clearance and volume of distribution at steady state of Grepafloxacin were significantly decreased to 60 and 63 % of the corresponding control values by cyclosporin A. The apparent oral clearance of Grepafloxacin was decreased to 33 % of the control, and the bioavailability of Grepafloxacin was increased to 95 % by cyclo-sporin A from 53 % in the controls. Intestinal clearance of Grepafloxacin and levofloxacin were decreased to one-half and one-third of the control, respectively, and biliary clearance o
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Pharmacokinetic Role of P-Glycoprotein in Oral Bioavailability and Intestinal Secretion of Grepafloxacin in Vivo
Journal of Pharmacology and Experimental Therapeutics, 2002Co-Authors: Hiroaki Yamaguchi, Ikuko Yano, Hideyuki SaitoAbstract:The purpose of this study was to clarify the contribution of P-glycoprotein to the bioavailability and intestinal secretion of Grepafloxacin and levofloxacin in vivo. Plasma concentrations of Grepafloxacin and levofloxacin after intravenous and intraintestinal administration were increased by cyclosporin A, a P-glycoprotein inhibitor, in rats. The total body clearance and volume of distribution at steady state of Grepafloxacin were significantly decreased to 60 and 63% of the corresponding control values by cyclosporin A. The apparent oral clearance of Grepafloxacin was decreased to 33% of the control, and the bioavailability of Grepafloxacin was increased to 95% by cyclosporin A from 53% in the controls. Intestinal clearance of Grepafloxacin and levofloxacin were decreased to one-half and one-third of the control, respectively, and biliary clearance of Grepafloxacin was also decreased to one-third with cyclosporin A in rats. Intestinal secretion of Grepafloxacin in mdr1a/1b (−/−) mice, which lack mdr1 -type P-glycoproteins, was significantly decreased compared with wild-type mice, although the biliary secretion was similar. Intestinal secretion of Grepafloxacin in wild-type mice treated with cyclosporin A was comparable to those in mdr1a/1b (−/−) mice with or without cyclosporin A, indicating that cyclosporin A completely inhibited P-glycoprotein-mediated intestinal transport of Grepafloxacin. In conclusion, our results indicated that P-glycoprotein mediated the intestinal secretion of Grepafloxacin and limited the bioavailability of this drug in vivo.
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Transport characteristics of Grepafloxacin and levofloxacin in the human intestinal cell line Caco-2.
European journal of pharmacology, 2001Co-Authors: Hiroaki Yamaguchi, Hideyuki Saito, Ikuko Yano, Kenichi InuiAbstract:Transport characteristics of Grepafloxacin and levofloxacin across the apical membrane of Caco-2 cells were examined. Both Grepafloxacin and levofloxacin uptakes increased rapidly, and were temperature-dependent. Grepafloxacin and levofloxacin uptakes showed concentration-dependent saturation with Michaelis constants of 3.9 and 9.3 mM, respectively. Uptake of Grepafloxacin and levofloxacin increased in Cl(-)-free and ATP depleted conditions, suggesting the involvement of an efflux transport system different from the uptake mechanism. However, cyclosporin A, a typical inhibitor of P-glycoprotein, did not affect the uptake of these drugs. Unlabeled Grepafloxacin, unlabeled levofloxacin and quinidine inhibited the uptake of Grepafloxacin and levofloxacin under Cl(-)-free conditions. Tetraethylammonium, cimetidine, p-aminohippurate, probenecid, amino acids, beta-lactam antibiotic or monocarboxylates did not inhibit the uptake of Grepafloxacin and levofloxacin under the same conditions. In conclusion, our results suggested that Grepafloxacin and levofloxacin uptakes were mediated by a specific transport system distinct from those for organic cations and anions, amino acids, dipeptides and monocarboxylates.
