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Jinding Huang - One of the best experts on this subject based on the ideXlab platform.
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Inhibition of the Intestinal digoxin absorption and exsorption by quinidine.
Drug Metabolism and Disposition, 1996Co-Authors: Sheng-fang Su, Jinding HuangAbstract:Digoxin-quinidine interaction is well documented in the literature. The mechanism is, however, unknown. Previously, it was shown that quinidine reduced digoxin secretion by inhibiting P-glycoprotein (Pgp) in the renal tubule. Because Pgp is expressed in the small intestine to an extent no less than that in the kidney, the study was designed to investigate the possible effect of quinidine on the absorption and exsorption of digoxin in the rat intestine. Results from the everted sac study using different Pgp inhibitors and inducers support that digoxin is a substrate of Pgp in both jejunum and ileum. Plasma concentration of digoxin after intravenous administration increased 2-fold when 1 mg/hr quinidine was coinfused, whereas the amount that appeared in the Intestinal lumen decreased by approximately 40%. In the presence of quinidine, total Clearance decreased from 318.0 +/- 19.3 to 167.1 +/- 11.0 ml/hr, whereas Intestinal Clearance decreased from 28.8 +/- 1.7 to 11.1 +/- 1.6 ml/hr. In a separate study, 3H-labeled digoxin was infused intravenously together with luminal perfusion of unlabeled digoxin in the intestine. The change of 3H-labeled digoxin concentrations in plasma and in the Intestinal lumen was similar to those in the exsorption study. However, concentration of unlabeled digoxin in plasma or the Intestinal lumen did not alter significantly with the addition of quinidine. The absorption Clearance in the control group (N = 6, 6.4 +/- 0.47 ml/hr) was significantly higher than that in the group with quinidine coadministration (N = 6, 4.8 +/- 0.31 ml/hr; p < 0.05). This indicates that quinidine may affect not only the elimination of digoxin, such as renal secretion, but also the absorption/exsorption of digoxin in the gastroIntestinal tract. This study suggests that Pgp is involved in the drug interaction between digoxin and quinidine in the small intestine. It is clinically important to understand the effect of quinidine on digoxin absorption for further assessment.
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Inhibition of Intestinal P-glycoprotein and effects on etoposide absorption.
Cancer Chemotherapy and Pharmacology, 1995Co-Authors: Jinding HuangAbstract:P-glycoprotein (Pgp) actively pumps a number of antineoplastic drugs, such as etoposide, out of cancer cells and causes multidrug resistance. Pgp is also expressed at the brush-border membrane of the small intestine under normal physiological conditions. We hypothesized that inhibition of Intestinal Pgp might decrease the efflux of etoposide from the blood into the Intestinal lumen, thereby, increasing the bioavailability of etoposide. The absorption of etoposide was studied using everted gut sacs prepared from rat jejunum and ileum. The addition of C219, a monoclonal antibody of Pgp, at 100 ng/ml or of 0.2 M 5′-adenylylimidodiphosphate, a nonhydrolyzable adenosine triphosphate (ATP) analog, increased the absorption of etoposide. Quinidine, an antiarrythmic agent, has been demonstrated to circumvent multidrug resistance in cell lines, possibly by interfering with Pgp function. Adding quinidine at 1 mg/ml to the everted gut sac increased the absorption of etoposide. In vivo absorption of etoposide was also studied by intraluminal perfusion of the drug in the small intestine of anesthetized rats. Intravenous infusion of quinidine at either 1 or 2 mg/h increased the serum level of etoposide in a dose-dependent manner. Intravenous infusion of etoposide at 0.2 mg/h resulted in luminal exsorption of the drug in the small intestine. The Intestinal Clearance of etoposide was 41.7 ± 7.2 ml kg−1, which decreased to 18.4 ± 3.9 ml kg−1 with the infusion of quinidine at 1 mg/h. The present data confirm that Intestinal Pgp mediates the efflux of etoposide and that the use of Pgp-inhibiting agents such as quinidine may increase the bioavailability of etoposide.
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Induction and Inhibition of Intestinal P-glycoprotein and Effects on Etoposide Absorption
Drug Metabolism and Pharmacokinetics, 1993Co-Authors: Jinding HuangAbstract:P-Glycoprotein (Pgp) actively pumps a number of antineoplastic drugs, such as etoposide, out of cancer cells and causes multidrug resistance. Pgp also expresses at the brush border membrane of the small intestine under the normal physiologic condition. We hypothesized that induction or inhibition of Intestinal Pgp might increase or decrease the etoposide efflux from blood into the Intestinal lumen and, therefore, decrease or increase the absorption of etoposide, respectively. Etoposide absorption was studied using an everted gut sac preparation of rat jejunum and ileum. In this study, we found that treating rats with sodium arsenite (10 μg/kg), sodium butyrate (0.5 mg/kg), or 3-methylcholanthrene (3-MC, 170 μg/kg) for 5 days decreased the Intestinal absorption of etoposide in both jejunum and ileum. Western blotting with C219, a monoclonal antibody of Pgp, confirmed the increase of the Intestinal Pgp in both ileum and jejunum. With reversed-transcription/polymerase chain reaction of rat mdrlb gene, we found that arsenite and butyrate induction increased mdrlb mRNA in the jejunum, whereas the inducing effect of arsenite, butyrate, or 3-MC in the ileum was not significant. Addition of C219 at 0.1 U/ml or 5'-adenylylimidodiphosphate at 0.2 N, a non-hydrolyzable ATP analog, increased the absorption of etoposide. Quinidine, an antiarrythmics, has been demonstrated to circumvent the multidrug resistance in cell lines, possibly by interfering with Pgp function. Adding quinidine at 1 mg/ml to the everted gut sac preparation also substantially increased the absorption of etoposide. In situ absorption of etoposide was also studied by intraluminal perfusion of the drug in anesthetized rats. Intravenous infusion of quinidine at either 1 or 2 mg/hr both increased serum level of etoposide. Such an increase was shown to be dose-dependent. Intravenous infusion of etoposide at 0.2 mg/hr resulted in luminal exsorption of the drug in small intestine. The Intestinal Clearance rate of etoposide was 41.7±7.2 ml/hr/kg. When etoposide was administered at the same infusion rate with 1 mg/hr of quinidine, the Intestinal Clearance of etoposide decreased to 18.4±3.9 ml/hr/kg. These in situ data confirmed that the Intestinal Pgp mediated the efflux of etoposide and the use of Pgp-inhibiting agent such as quinidine may increase the Intestinal absorption of etoposide. In addition to etoposide, the efflux of rhodamine 123, which is a common substrate used to measure Pgp function, in the everted gut sacs was also studied. Despite of the Pgp level increase in both ileum and jejunun shown in Western blotting, rhodamine 123 efflux increased only in the jejunum, but not in the ileum. The results suggest that there are multiple members of Pgp family in the rat small intestine. Rhodamine 123 was probably transported by a Pgp encoded by mdrlb, and etoposide was transported by another Pgp member.
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Concentration-dependent exsorption of quinidine in the rat intestine.
Journal of Pharmacy and Pharmacology, 1992Co-Authors: Chihorng Bair, Ming Jer Tang, Jinding HuangAbstract:— During intravenous infusion, the luminal concentration of quinidine was higher than the plasma concentration. The Intestinal Clearance (CLi) of the drug was measured by dividing the rate of appearance of the drug in the Intestinal luminal perfusate by the plasma concentration. The CLi of quinidine was therefore much higher than the rate of luminal perfusion. Over the infusion dose range of 0·1–2 mg h−1, the CLi of quinidine decreased with increasing plasma concentration of quinidine. Adding quinidine into the luminal perfusate had little effect on the CLi of quinidine. Co-administration of quinidine with other agents intravenously did not alter the CLi of salicylic acid and urea, while the same treatment decreased the CLi of theophylline and 5-disopyramide. In-vitro experiments on brush-border membrane vesicles showed that quinidine decreased the rate of Na+ uptake and H+ efflux. The inhibition was significant at quinidine concentrations above 20 μm. Quinidine was a more potent inhibitor than amiloride. At quinidine infusion rates less than 2 mg h−1, quinidine concentration in plasma or in the luminal perfusate was at the lower limit of the inhibitory concentration. Microclimate pH at the Intestinal surface was also measured. At mid-jejunum, the microclimate pH increased 0·3 pH units by infusing 2 mg h−1 of quinidine, while the microclimate pH at most other measuring sites was not significantly altered by quinidine infusion. It was concluded that quinidine is exsorbed from blood into the Intestinal lumen by a carrier-mediated pathway in addition to the passive diffusion. At high plasma concentration, quinidine exsorption becomes saturated. Quinidine inhibited the Intestinal exsorption of theophylline and S-disopyramide possibly by competition on the carrier.
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effect of theophylline on the Intestinal Clearance of drugs in rats
Journal of Pharmacy and Pharmacology, 1992Co-Authors: Chihorng Bair, Jinding HuangAbstract:: Intestinal exsorption of salicylic acid, urea and quinidine was measured during the perfusion of the rat Intestinal lumen with Tyrode solution. The Intestinal Clearance (CLi) of the three compounds was measured by dividing the rate of appearance in the Intestinal luminal perfusate by the plasma concentration of the compound. Co-administration of theophylline (0.2 mg h-1) with the test agents increased the CLi of salicylic acid, did not alter the CLi of urea, but decreased the CLi of quinidine. The effect of theophylline on the CLi of quinidine was enhanced with increasing dose. Theophylline was found to increase microclimate-pH at the Intestinal surface, but the magnitude of delta pH alone could not explain the effect of theophylline on the CLi of quinidine. The data, together with previous observations, suggest that the Intestinal exsorption of drugs was affected by the microclimate pH and by the unstirred water layer. Theophylline affects CLi of salicylic acid and quinidine partly by increasing the microclimate pH of the intestine. Theophylline may also affect quinidine CLi by inhibiting the carrier-mediated pathway.
Robert Farinotti - One of the best experts on this subject based on the ideXlab platform.
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Active Intestinal elimination of ciprofloxacin in rats: modulation by different substrates.
British Journal of Pharmacology, 1999Co-Authors: S Dautrey, Claude Carbon, K Felice, A. Petiet, Bernard Lacour, Robert FarinottiAbstract:Two in vivo models, in the rat, were used to investigate, in the presence of different substrates, the overall and net Intestinal elimination of ciprofloxacin: an open-Intestinal perfusion model and an Intestinal loop model respectively. In the presence of quinidine, verapamil and cyclosporin (substrates of the P-glycoprotein (P-gp)), plasma AUCs of ciprofloxacin were 1.5–2 fold increased, while biliary Clearance (1.5–2 fold), Intestinal overall and net Clearances (2–4 fold and 1.5–8 fold respectively) decreased. The weak effect obtained with cyclosporin as compared to verapamil and especially quinidine, suggests, for ciprofloxacin, the existence of transport systems distinct from the P-gp, as the OCT1 transporter which could be inhibited by quinidine. With cephalexin and azlocillin, two β-lactam antibiotics, plasma AUCs of ciprofloxacin increased and biliary and Intestinal overall Clearances decreased in a similar fashion (1.3–2 fold), suggesting the involvement of organic anion and/or cation transporters. In the presence of structural analogues, the effect was dependent on the compound administered: Sparfloxacin had no effect on Intestinal Clearance of ciprofloxacin. In contrast, with pefloxacin, overall Intestinal Clearance of ciprofloxacin was decreased and net Intestinal Clearance increased. The specificity of ciprofloxacin Intestinal transport appears to be different from P-gp as outlined by the lack of competition with sparfloxacin, a P-gp substrate. Ciprofloxacin Intestinal elimination seems to be mediated by organic anion and/or cation transporters and a mechanism sensitive to quinidine and verapamil. British Journal of Pharmacology (1999) 127, 1728–1734; doi:10.1038/sj.bjp.0702703
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influence of renal failure on Intestinal Clearance of ciprofloxacin in rats
Antimicrobial Agents and Chemotherapy, 1999Co-Authors: S Dautrey, Lydia Rabbaa, Denise Laouari, B Lacour, Claude Carbon, Robert FarinottiAbstract:Following intravenous doses, ciprofloxacin pharmacokinetics in control and nephrectomized rats were studied. There were no differences between control and nephrectomized rats for area under the concentration-time curve in plasma or biliary Clearance. The Intestinal Clearance of ciprofloxacin was increased in nephrectomized rats. Intestinal elimination seems to compensate partially for the decrease in urinary excretion of ciprofloxacin in nephrectomized rats.
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Intestinal elimination of ofloxacin enantiomers in the rat: evidence of a carrier-mediated process.
Antimicrobial Agents and Chemotherapy, 1996Co-Authors: Lydia Rabbaa, S Dautrey, N. Colas-linhart, C Carbon, Robert FarinottiAbstract:The aim of this work was to examine the mechanism involved in Intestinal elimination of the two optical isomers of ofloxacin in the rat. An Intestinal segment was isolated in situ and perfused with saline, while drug solution was administered via the carotid artery. Blood samples and Intestinal effluents were collected and analyzed by a high-performance liquid chromatography method. We observed saturable and stereoselective Intestinal elimination of the ofloxacin enantiomers. The elimination process favored the R-(+) form of the molecule. After a parenteral dose of 20 mg of racemic ofloxacin per kg of body weight, Intestinal Clearances were 0.23 +/- 0.03 versus 0.30 +/- 0.03 ml/min for S-(-)- and R-(+)-ofloxacin, respectively. Ciprofloxacin and pefloxacin interfered with ofloxacin elimination and significantly reduced the Intestinal Clearance of S-(-)- and R-(+)-ofloxacin. With concomitant ciprofloxacin, Intestinal Clearances became 0.13 +/- 0.02 versus 0.17 +/- 0.03 ml/min and 0.14 +/- 0.01 versus 0.19 +/- 0.05 ml/min with pefloxacin for S-(-)- and R-(+)-ofloxacin, respectively. Those findings argue for the presence of a common transport system in the rat intestine with variable affinities for fluoroquinolones. In addition, verapamil and quinidine, two P-glycoprotein blockers, significantly reduced the Intestinal elimination of both ofloxacin isomers (with concomitant verapamil, Intestinal Clearances were 0.12 +/- 0.02 versus 0.18 +/- 0.03 ml/min for S-(-)- and R-(+)-ofloxacin, respectively, while with concomitant quinidine, values were 0.18 +/- 0.01 versus 0.23 +/- 0.01 ml/min without modifying their areas under the concentration-time curve in serum. Similar results were found with another fluoroquinolone, ciprofloxacin, in previous work. P-glycoprotein appears to be involved in the Intestinal elimination of fluoroquinolones in rats. The characterization of fluoroquinolone Intestinal elimination has significant clinical relevance for the better evaluation of the influence of this secretory pathway on antibiotic efficacy and selection of resistant bacteria within the Intestinal flora.
Robert T Foster - One of the best experts on this subject based on the ideXlab platform.
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renal biliary and Intestinal Clearance of sotalol enantiomers in rat model evidence of Intestinal exsorption
Biopharmaceutics & Drug Disposition, 1996Co-Authors: Robert A Carr, Franco M Pasutto, Robert T FosterAbstract:: Biliary Clearance (Clb) of sotalol (STL) enantiomers was assessed in anaesthetized Sprague-Dawley rats (419 +/- 9 g, mean +/- SEM, n = 4) following administration of a 10 mg kg-1 i.v. dose of the racemate. Clb for S- and R-STL (0.0675 +/- 0.0090 and 0.0662 +/- 0.0089 mL min-1 kg-1, respectively) represented approximately 0.3% of systemic Clearance (Cls) values for S- and R-STL (20.4 +/- 2.2 and 20.7 +/- 2.0 mL min-1 kg-1, respectively). Bile:plasma concentration ratios at 1, 2, and 3 h post-dose were approximately 1.4, 1.3, and 1.2 for both STL enantiomers. Renal Clearance (Clr) and Intestinal Clearance (Cli) of STL enantiomers were assessed in conscious Sprague-Dawley rats (325 g, n = 4) following administration of a 10 mg kg-1 i.v. dose of the racemate. STL enantiomers were predominantly eliminated intact in the urine: Clr for S- and R-STL (26.3 +/- 3.2 and 28.7 +/- 4.2 mL min-1 kg-1 respectively) accounted for approximately 96% of Cls for S- and R-STL (27.5 +/- 3.3 and 29.9 +/- 4.2 mL min-1 kg-1, respectively). Approximately 4% of the dose was recovered in the faeces, corresponding to Cli values of 1.16 +/- 0.17 and 1.26 +/- 0.19 mL min-1 kg-1 for S- and R-STL, respectively. Total recovery of the administered dose in urine and faeces was 99.7 +/- 0.2 and 99.8 +/- 0.5% for S- and R-STL, respectively. It is concluded from these results in the rat model that (i) STL enantiomers are predominantly eliminated intact in urine; (ii) STL enantiomers are excreted intact in bile, and to a much larger extent in the faeces, thus suggesting the presence of Intestinal exsorption of STL; (iii) STL does not appear to be metabolized; and (iv) Cls, Clr, Clb, and Cli are negligibly stereoselective.
Takaaki Hasegawa - One of the best experts on this subject based on the ideXlab platform.
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effect of shiga like toxin ii from escherichia coli o157 h7 on Intestinal Clearance of norfloxacin in rats
Life Sciences, 2006Co-Authors: Hironao Nakayama, Kiyoyuki Kitaichi, Hiroaki Kanazawa, Mai Ando, Yohei Fujimoto, Kenji Takagi, Kenzo Takagi, Takaaki HasegawaAbstract:Enterohemorrhagic Escherichia coli (EHEC) O157:H7 infection causes severe clinical symptoms, due to its bacterial toxin, called Shiga-like toxin (SLT). However, little is known about the information to establish a safe and efficient prescription to treat for EHEC O157:H7 patients. Thus, we investigated the effect of SLT-II on Intestinal function in rats by using the antibiotic norfloxacin (NFLX) as a model drug. The Intestinal Clearance (CLi) of NFLX, determined by loop method in the jejunum, was significantly decreased by SLT-II. In histopathological experiment, epithalaxia was observed in SLT-II-treated rats without structural changes of tight junction suggesting the deterioration of active transport systems by SLT-II. CLi of NFLX in normal rats was decreased by carnitine (CAR), suggesting the possible involvement of CAR-sensitive transporter in CLi of NFLX. Taken together, these results suggest that the EHEC O157:H7 infection might affect the Intestinal disposition of NFLX due to the changing Intestinal expression/function of drug transporters by SLT-II.
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Possible Involvement of the Drug Transporters P Glycoprotein and Multidrug Resistance-Associated Protein Mrp2 in Disposition of Azithromycin
Antimicrobial Agents and Chemotherapy, 2004Co-Authors: Masami Sugie, Kiyoyuki Kitaichi, Kenji Takagi, Kenzo Takagi, Emiko Asakura, Ying Lan Zhao, Shoko Torita, Masayuki Nadai, Kenji Baba, Takaaki HasegawaAbstract:P glycoprotein and multidrug resistance-associated protein 2 (Mrp2), ATP-dependent membrane transporters, exist in a variety of normal tissues and play important roles in the disposition of various drugs. The present study seeks to clarify the contribution of P glycoprotein and/or Mrp2 to the disposition of azithromycin in rats. The disappearance of azithromycin from plasma after intravenous administration was significantly delayed in rats treated with intravenous injection of cyclosporine, a P-glycoprotein inhibitor, but was normal in rats pretreated with intraperitoneal injection erythromycin, a CYP3A4 inhibitor. When rats received an infusion of azithromycin, cyclosporine and probenecid, a validated Mrp2 inhibitor, significantly decreased the steady-state biliary Clearance of azithromycin to 5 and 40% of the corresponding control values, respectively. However, both inhibitors did not alter the renal Clearance of azithromycin, suggesting the lack of renal tubular secretion of azithromycin. Tissue distribution experiments showed that azithromycin is distributed largely into the liver, kidney, and lung, whereas both inhibitors did not alter the tissue-to-plasma concentration ratio of azithromycin. Significant reduction in the biliary excretion of azithromycin was observed in Eisai hyperbilirubinemic rats, which have a hereditary deficiency in Mrp2. An in situ closed-loop experiment showed that azithromycin was excreted from the blood into the gut lumen, and the Intestinal Clearance of azithromycin was significantly decreased by the presence of cyclosporine in the loop. These results suggest that azithromycin is a substrate for both P glycoprotein and Mrp2 and that the biliary and Intestinal excretion of azithromycin is mediated via these two drug transporters.
Chihorng Bair - One of the best experts on this subject based on the ideXlab platform.
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Concentration-dependent exsorption of quinidine in the rat intestine.
Journal of Pharmacy and Pharmacology, 1992Co-Authors: Chihorng Bair, Ming Jer Tang, Jinding HuangAbstract:— During intravenous infusion, the luminal concentration of quinidine was higher than the plasma concentration. The Intestinal Clearance (CLi) of the drug was measured by dividing the rate of appearance of the drug in the Intestinal luminal perfusate by the plasma concentration. The CLi of quinidine was therefore much higher than the rate of luminal perfusion. Over the infusion dose range of 0·1–2 mg h−1, the CLi of quinidine decreased with increasing plasma concentration of quinidine. Adding quinidine into the luminal perfusate had little effect on the CLi of quinidine. Co-administration of quinidine with other agents intravenously did not alter the CLi of salicylic acid and urea, while the same treatment decreased the CLi of theophylline and 5-disopyramide. In-vitro experiments on brush-border membrane vesicles showed that quinidine decreased the rate of Na+ uptake and H+ efflux. The inhibition was significant at quinidine concentrations above 20 μm. Quinidine was a more potent inhibitor than amiloride. At quinidine infusion rates less than 2 mg h−1, quinidine concentration in plasma or in the luminal perfusate was at the lower limit of the inhibitory concentration. Microclimate pH at the Intestinal surface was also measured. At mid-jejunum, the microclimate pH increased 0·3 pH units by infusing 2 mg h−1 of quinidine, while the microclimate pH at most other measuring sites was not significantly altered by quinidine infusion. It was concluded that quinidine is exsorbed from blood into the Intestinal lumen by a carrier-mediated pathway in addition to the passive diffusion. At high plasma concentration, quinidine exsorption becomes saturated. Quinidine inhibited the Intestinal exsorption of theophylline and S-disopyramide possibly by competition on the carrier.
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effect of theophylline on the Intestinal Clearance of drugs in rats
Journal of Pharmacy and Pharmacology, 1992Co-Authors: Chihorng Bair, Jinding HuangAbstract:: Intestinal exsorption of salicylic acid, urea and quinidine was measured during the perfusion of the rat Intestinal lumen with Tyrode solution. The Intestinal Clearance (CLi) of the three compounds was measured by dividing the rate of appearance in the Intestinal luminal perfusate by the plasma concentration of the compound. Co-administration of theophylline (0.2 mg h-1) with the test agents increased the CLi of salicylic acid, did not alter the CLi of urea, but decreased the CLi of quinidine. The effect of theophylline on the CLi of quinidine was enhanced with increasing dose. Theophylline was found to increase microclimate-pH at the Intestinal surface, but the magnitude of delta pH alone could not explain the effect of theophylline on the CLi of quinidine. The data, together with previous observations, suggest that the Intestinal exsorption of drugs was affected by the microclimate pH and by the unstirred water layer. Theophylline affects CLi of salicylic acid and quinidine partly by increasing the microclimate pH of the intestine. Theophylline may also affect quinidine CLi by inhibiting the carrier-mediated pathway.
