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ABSTRACT: Curcumin, a major component of the food spice turmeric (Curcuma longa), has multiple beneficial effects on diseases of the liver and bile duct. We have investigated whether modulation of the curcumin elimination pathway could increase its hepatic and biliary exposure in rats.
Probenecid, an inhibitor of the metabolism and biliary excretion of curcumin, was used as a modulator. After intravenous administration of curcumin at a dose of 18 mg/kg/h without (control) or with co-infusion of probenecid (230 mg/kg/h) in rats, the pharmacokinetic parameters of curcumin were estimated.
Coadministration of probenecid significantly increased the total area under the plasma (1.88-fold) and bile (6.73-fold) concentration-time curves from 0 to 80 min of curcumin relative to those in the controls. The tissue-to-plasma concentration ratio in the liver was also dramatically increased (69.3-fold) by probenecid. These results may be attributed to the dual inhibitory effects of probenecid, to a greater extent, on metabolism via glucuronidation, and to a lesser extent, on the biliary excretion of curcumin via the multidrug resistance-associated protein 2.
The probenecid-mediated increase in hepatic and biliary exposure of curcumin suggested that the use of combination drug regimens involving curcumin and modulators of elimination may be an innovative approach for the therapeutic use of curcumin.
The Journal of pharmacy and pharmacology. 03/2013; 65(3):423-9.
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ABSTRACT: A simple and sensitive liquid chromatography-tandem mass spectrometry method was developed and validated in rat plasma for quantification of tadalafil, a novel therapeutic agent for erectile dysfunction. Tadalafil and acebutolol (internal standard) were extracted by liquid-liquid extraction with tert-butyl methyl ether. The chromatographic separation was performed on a reverse phase C(18) column with a mobile phase consisting of 0.1 % formic acid and acetonitrile (45:55, v/v) at a flow rate of 0.3 mL/min. The protonated analyte was quantitated by multiple reaction monitoring with a Waters Quattro micro™ API mass spectrometer. The calibration curve was linear over a concentration range of 2-2000 ng/mL, and the lower limit of quantification was 2 ng/mL with a precision (CV %) of 10.9 %. Acceptable intra-day and inter-day precision and accuracy were obtained at 3 concentration levels (3, 200, and 1500 ng/mL). Tadalafil was found to be stable in a battery of studies, including bench top, freeze-thaw, and autosampler conditions. The validated method was successfully used to determine tadalafil concentration in rat plasma samples after oral administration at a dose of 1 mg/kg.
Archives of Pharmacal Research 02/2013; · 1.59 Impact Factor
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ABSTRACT: In this study, we investigated pharmacokinetic drug interactions of clopidogrel with P-gp inhibitors in rats and dogs. Following the oral administration of clopidogrel with or without the P-gp inhibitors, quercetin (250 mg/kg), telmisartan (8 mg/kg), and cyclosporine A (10 mg/kg), in rats and dogs, the plasma concentration-time profiles of clopidogrel carboxylic acid, a surrogate marker for the bioavailability of clopidogrel, were determined. Co-administration of the quercetin, telmisartan and cyclosporine A significantly increased the area under the curve and peak plasma concentration of clopidogrel carboxylic acid in rats. However, in dogs, the plasma concentrations of clopidogrel carboxylic acid were not considerably changed by the coadministration of three different kinds of P-gp inhibitors. These findings suggest potential interaction of clopidogrel with quercetin, telmisartan, and cyclosporine A, although there are differences between animal models. Follow-up clinical study is needed to explore the meaning of this remarkable species differences in the P-gp-mediated interaction.
Archives of Pharmacal Research 10/2012; 35(10):1831-7. · 1.59 Impact Factor
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ABSTRACT: Purpose. Hyperlipidemia is associated with an increased risk of erectile dysfunction. In this study, we investigated the effects of hyperlipidemia on the pharmacokinetics of tadalafil, a novel therapeutic agent for erectile dysfunction, in rats with experimental hyperlipidemia. Methods. Tadalafil (1 mg/kg) was administered to control rats and rats with poloxamer-407-induced hyperlipidemia (1 g/kg, i.p.). In addition, we performed in vitro studies to determine the hepatic metabolism in S9 fractions, intestinal absorption, and plasma protein binding. Results. Hyperlipidemia dramatically increased tadalafil's the total area under the plasma concentration-time curve from time 0 to infinity after intravenous (2.09-fold) and oral (11.9-fold) administration, and decreased total body clearance (0.537-fold) and apparent volume of distribution at the steady state (0.438-fold) after intravenous administration of tadalafil. Further, we observed decreased in vitro hepatic S9 metabolism, intestinal first-pass metabolism, and unbound fraction of tadalafil. Conclusions. The alterations in the pharmacokinetics of tadalafil observed in rats with poloxamer 407-induced hyperlipidemia may be attributable to a decrease in hepatic and intestinal metabolism and unbound fraction of tadalafil in the plasma. These findings have potential therapeutic implications for predicting the pharmacokinetic responses of humans to hyperlipidemia. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.
Journal of pharmacy & pharmaceutical sciences: a publication of the Canadian Society for Pharmaceutical Sciences, Societe canadienne des sciences pharmaceutiques 09/2012; 15(4):528-37. · 1.65 Impact Factor
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ABSTRACT: The pharmacokinetics of paclitaxel and docetaxel were compared in diabetic rats induced by streptozotocin (DMIS rats) and the impact of altered expression of cytochrome P450 3A (Cyp3A) and P-glycoprotein (P-gp) in the diabetic state. The pharmacokinetics of paclitaxel and docetaxel were determined after intravenous (5 mg/kg) and oral (30 and 40 mg/kg, respectively) administration to both groups and the mRNA expression levels of Cyp3A isozymes and Mdr1a and Mdr1b in the liver and small intestine were determined in control and DMIS rats. After intravenous administration, the AUC and clearance of paclitaxel and docetaxel were not significantly different in DMIS vs control rats. After oral administration, the AUC and C(max) of paclitaxel in DMIS rats were significantly greater than those in the control rats, whereas those of docetaxel was not changed significantly. The mRNA expression levels of hepatic Cyp3A1, Cyp3A9 and Mdr1b were significantly increased in DMIS compared with the control rats. In the intestine, Cyp3A62 expression decreased in the DMIS rats compared with the controls. Thus the pharmacokinetic changes of taxanes observed in the DMIS rats were attributed to changes in P-gp and Cyp3A, predominant factors that control the absorption of paclitaxel and docetaxel, respectively. It seemed that there were different susceptibilities to intestinal P-gp and Cyp3A between the two taxanes. Copyright © 2012 John Wiley & Sons, Ltd.
Biopharmaceutics & Drug Disposition 08/2012; 33(8):474-86. · 2.07 Impact Factor
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ABSTRACT: Curcumin and quercetin are natural compounds with a wide spectrum of activities, including antioxidant and anticancer activities. In this study, the combined effect of the two compounds was investigated, with special emphasis on the pharmacokinetics of curcumin by the quercetin-induced changes in the albumin binding of curcumin. We evaluated the effect of quercetin on the binding of curcumin to albumin and on the uptake of curcumin into the cells of the human colon carcinoma cell line WiDr. In addition, we also investigated changes in the in vivo pharmacokinetics of curcumin and curcumin sulfate (the major metabolite of curcumin) coadministered with quercetin. We found that quercetin inhibited the binding of curcumin to albumin and increased the uptake of curcumin into WiDr cells, the human colon carcinoma cell. The quercetin-induced increased uptake (1.6-fold) of curcumin into WiDr cells was also confirmed by an ex vivo study. The in vivo pharmacokinetics of curcumin showed obvious changes when it was coadministered with quercetin, with the significantly lower plasma concentration and greater biliary excretion of curcumin and curcumin sulfate. The present study suggests that quercetin could enhance the cellular uptake of curcumin and modulate in vivo pharmacokinetics of curcumin, and it could be related to albumin-binding interaction.
Drug metabolism and disposition: the biological fate of chemicals 05/2012; 40(8):1452-5. · 3.74 Impact Factor
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ABSTRACT: Decursin is considered the major bioactive compound of Angelica gigas roots, a popular Oriental herb and dietary supplement. In this study, the pharmacokinetics of decursin and its active metabolite, decursinol, were evaluated after the administration of decursin in rats. The plasma concentration of decursin decreased rapidly, with an initial half-life of 0.05 h. It was not detectable at 1 h after intravenous administration at an area under the plasma concentration-time curve of 1.20 µg · mL-1·h, whereas the concentration of decursinol increased rapidly reaching a maximum concentration of 2.48 µg · mL-1 at the time to maximum plasma concentration of 0.25 h and an area under the plasma concentration-time curve of 5.23 µg · mL-1·h. Interestingly, after oral administration of decursin, only decursinol was present in plasma, suggesting an extensive hepatic first-pass metabolism of decursin. The extremely low bioavailability of decursin after its administration via the hepatic portal vein (the fraction of dose escaping first-pass elimination in the liver, FH = 0.11) is indicative of extensive hepatic first-pass metabolism of decursin, which was confirmed by a tissue distribution study. These findings suggest that decursin is not directly associated with the bioactivity of A. gigas and that it may work as a type of natural prodrug of decursinol.
Planta Medica 05/2012; 78(9):909-13. · 2.15 Impact Factor
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ABSTRACT: Curcumin has a wide spectrum of pharmacological activities, including antioxidant, anti-inflammatory, antimicrobial, and anticancer properties. Recently, its potential as effective chemoprevention against cholangiocarcinoma, a highly malignant tumor of the bile duct with limited therapeutic options, was reported. The purpose of the present study was to investigate the contribution of multidrug resistance-associated protein 2 (Mrp2) to the biliary excretion of curcumin using Sprague-Dawley rats (SDR) and Eisai hyperbilirubinemic rats (EHBR). After intravenous administration of curcumin with a loading dose of 4.5 mg/kg, followed by a constant infusion of 18 mg/kg/h to the SDR and EHBR, the pharmacokinetic parameters of curcumin were estimated. In EHBR, the total area under the bile concentration-time curve from 0 to 80 min following curcumin administration was dramatically decreased (0.094%) compared to that in SDR. In addition, the plasma-to-bile and liver-to-bile clearances were both significantly decreased compared to SDR. These results provide the first evidence that Mrp2 mediates the biliary excretion of curcumin and thus may be a major factor in the control of exposure of curcumin to the bile duct. This study may be helpful to the potential use of curcumin as a treatment for bile duct cancer, and to understanding the genetic polymorphism of Mrp2 for clinical trials of curcumin.
Biological & Pharmaceutical Bulletin 01/2012; 35(5):777-80. · 1.66 Impact Factor
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ABSTRACT: Renal organic anion transport systems play an important role in the excretion of anionic drugs and toxic compounds. Probenecid has been used as a potent inhibitor of urinary and biliary excretion of anionic compounds mediated by transporters such as organic anion transporters and multidrug resistance-associated protein 2 (Mrp2). The purpose of this study was to optimize the dose of probenecid required for selective inhibition of urinary excretion of anionic compounds in rats, without inhibition of biliary excretion. Phenolsulfonphthalein (PSP), a model anionic compound that is excreted in urine and bile, was intravenously administered to rats after intraperitoneal injection of different doses of probenecid (0, 0.2, 2, 10, 100, 200 and 400 mg kg(-1) ). Treatment with 100, 200 or 400 mg kg(-1) probenecid decreased both renal clearance (CL(r) ) and biliary clearance (CL(b) ) of PSP, whereas 0.2 mg kg(-1) probenecid did not have any effect. Probenecid administered at doses of 2 and 10 mg kg(-1) decreased only CL(r) . The median effective doses of probenecid for inhibiting CL(r) and CL(b) were 0.925 and 23.9 mg kg(-1) , respectively. These data suggest that a low dose of probenecid selectively inhibits urinary excretion of PSP that may be mediated by organic anion transporters, without affecting biliary excretion that may be mediated by Mrp2. Copyright © 2011 John Wiley & Sons, Ltd.
Journal of Applied Toxicology 12/2011; · 2.48 Impact Factor
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ABSTRACT: We investigated the effects of naringin, naringenin and quercetin on the pharmacokinetics of doxorubicin in rats. These Citrus flavonoids are known as P-glycoprotein (P-gp) inhibitors and thus suspected to interact with doxorubicin, as shown by in vitro cell studies. Plasma concentrations, tissue distribution, and the urinary and biliary excretion of doxorubicin after intravenous infusion were investigated in rats followed by oral administration of Citrus flavonoids. To evaluate the impact of the biotransformation of Citrus flavonoids on the P-gp inhibition, the inhibitory effects of quercetin and its metabolite on P-gp were compared using ex vivo analysis. Contrary to previous in vitro results, the plasma concentration, biliary and urinary clearance, and tissue distribution of doxorubicin were not altered by pre-treatment with naringin and naringenin. Biliary clearance and urinary clearance were slightly decreased by quercetin, but there was no statistical difference. The minor effects of these flavonoids may relate to their low systemic concentration, due to the biotransformation in vivo situation. S9 stability assay and calcein accumulation assay showed that quercetin was a metabolically unstable compound, and the inhibitory effect of its metabolites on P-gp was negligible. In conclusion, naringin, naringenin and quercetin did not affect the in vivo pharmacokinetics of intravenously administered doxorubicin.
Pharmazie 06/2011; 66(6):424-9. · 1.01 Impact Factor
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ABSTRACT: Hyperlipidaemia correlates with an increased risk of occurrence of various cancers. In this study, the effects of hyperlipidaemia on the pharmacokinetics of docetaxel, a member of the taxane class of anti-cancer drugs, were investigated in rats with experimental hyperlipidaemia; we focused on the alterations in docetaxel metabolism and plasma distribution. Docetaxel (5 mg/kg intravenously (i.v.) and 40 mg/kg per oral (p.o.)) was administered to control rats and rats with poloxamer-407 (P-407)-induced hyperlipidaemia (1 g/kg, intraperitoneally). In vitro studies were conducted on hepatic metabolism in S9 fractions and plasma protein binding using the ultrafiltration method. Hyperlipidaemia dramatically increased the area under the plasma concentration-time curve from time 0 to infinity (AUC(0-∞)) of docetaxel after i.v. (1.86-fold) or p.o. (10.8-fold) administration and decreased total body clearance (0.574-fold) and apparent volume of distribution at steady state (0.615-fold) of docetaxel after i.v. administration. Compared with the control rats, the metabolism of docetaxel by hepatic S9 fractions and the unbound fraction in the plasma in the hyperlipidaemic rats were decreased, i.e., by 20.1 and 79.8%, respectively. In conclusion, the alterations in docetaxel pharmacokinetics in rats with P-407-induced hyperlipidaemia may be due, at least in part, to a decrease in hepatic metabolism and the unbound fraction of docetaxel in the plasma. These findings have potential therapeutic implications for predicting human pharmacokinetic responses to hyperlipidaemia.
Xenobiotica 05/2011; 41(9):797-804. · 1.79 Impact Factor
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ABSTRACT: Danshen (Salvia miltiorrhiza) contains tanshinones, which inhibit P-glycoprotein (P-gp) and the cytochrome P450 (CYP) system. In the present study, we evaluated the possible pharmacokinetic interactions of Danshen extract with docetaxel and clopidogrel in rats. Docetaxel (5 mg/kg intravenously and 40 mg/kg orally) or clopidogrel (30 mg/kg orally) was administered to rats with or without oral co-administration of Danshen (400 mg/kg). Co-administration of Danshen did not affect the plasma concentration profiles and pharmacokinetic parameters of docetaxel and clopidogrel, whereas cyclosporine A, a P-gp and CYP3A inhibitor, significantly influenced the pharmacokinetics of co-administered docetaxel and clopidogrel. Orally administered Danshen had no substantial effect on the pharmacokinetics of docetaxel and clopidogrel, suggesting the negligible safety concern of Danshen in P-gp- and CYP3A-mediated interactions in vivo.
International journal of pharmaceutics 03/2011; 410(1-2):68-74. · 2.96 Impact Factor
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ABSTRACT: Hwang-Ryun-Hae-Dok-Tang (HT; a standardized herbal formula consisting of extracts from Coptidis Rhizoma, Scutellariae Radix, Phellodendri Cortex, and Gardeniae Fructus) was reported to modulate a function of multidrug resistance associated protein 2 (Mrp2) in vitro. The aim of this study was to assess the in vivo pharmacokinetic interactions between HT and phenolsulfonphthalein (PSP), a typical model Mrp2 substrate eliminated via bile through Mrp2 in rats. Rats received intravenous PSP (0.8 mg/kg) followed by either a single oral dose of HT (0.42 g/kg) or multiple oral doses of HT (0.42 g/kg for 7 days). The effect of HT treatment was also investigated at a steady-state after intravenous PSP infusion. In contrast to previous in vitro results, in this study, we found that the HT-treated and control groups did not show any significant difference in the plasma PSP concentration and pharmacokinetic parameters, including area under the plasma concentration-time curve (AUC; control: 118 ± 19, single dose: 116 ± 40, and multiple dose: 137 ± 4, in mg/(min·mL)) and biliary clearance (control: 3.15 ± 0.69, single dose: 2.59 ± 1.11, and multiple dose: 2.53 ± 0.65, in mL/(min·kg)). However, cyclosporine A (5 mg/kg, an inhibitor of Mrp2) significantly decreased the AUC and biliary clearance of PSP. The steady-state plasma concentration and biliary clearance of PSP-were also similar between the groups. Taken together, our results suggest that HT may not be affected by Mrp2-mediated herb-drug interaction in vivo.
Archives of Pharmacal Research 12/2010; 33(12):2025-31. · 1.59 Impact Factor
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ABSTRACT: It has been reported that urinary excretion of two metabolites of valproic acid (VPA), 4-ene-valproic acid (4-VPA)and 2,4-diene-valproic acid (2,4-VPA), increased exponentially with the administration of high doses of VPA, and this increased formation of toxic metabolites could be related to VPA hepatotoxicity in humans. The aim of this study was to investigate whether the plasma level of 4-VPA and 2,4-VPA in rats corresponds to the urinary data for the same metabolites in humans.After the oral administration of VPA at doses of 20, 100 and 500 mg kg-1 in rats, the AUC0–24 h, 4-VPA/AUC0–24 h, VPA ratios (0.0399,0.0120 and 0.0100 for 20, 100 and 500 mg kg-1, respectively) and AUC0–24 h, 2,4-VPA/AUC0–24 h, VPA ratios (0.00104, 0.00201 and 0.00141, respectively) did not increase with increasing doses of VPA in rats. Thus, the plasma exposure of toxic metabolites normalized by dose remained unchanged (for 2,4-VPA) or even decreased (for 4-VPA) following high-dose VPA administration;this contradicts the findings of previous studies. Our results suggest that toxicity induced by high doses of VPA cannot be explained by a nonlinear increase of toxic metabolites in rats.
Journal of Applied Toxicology 11/2010; 30(8):775-8. · 2.48 Impact Factor
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ABSTRACT: The aim of this study was to investigate the effect of anesthesia on the pharmacokinetics of bromosulfophthalein (BSP) with focus on biliary clearance. The plasma concentration profile and biliary clearance of intravenously administered BSP was compared in conscious freely moving bile duct catheterized rats and rats anesthetized with ketamine or Zoletil. The plasma concentration of BSP in conscious rats was similar to that of anesthetized rats, irrespective of the anesthetic used. There was no significant difference in the volume of distribution, total body clearance and mean residence time of BSP between the groups. The biliary clearance of BSP in rats anesthetized using ketamine or Zoletil was also similar to that of conscious rats. Only bile flow was increased under anesthetization compared with conscious rats. These results demonstrate that the pharmacokinetics of BSP, including biliary clearance, in ketamine or Zoletil anesthetized rats is virtually identical to that in conscious rats and it may be related to blood flow limited hepatic disposition of BSP. Furthermore, they suggest the conscious rat model does not offer methodological advantage and the anesthesia model is suitable for a realistic approximation of the hepatobiliary transport of BSP.
Biopharmaceutics & Drug Disposition 04/2009; 30(2):94-8. · 2.07 Impact Factor
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ABSTRACT: The individual and combined antistress effects of the fruit of Schizandra chinensis and the radix of Scutellaria baicalensis were evaluated using a mouse acute stress model. Stress consisted of immobilization and electric foot shocks over 5 days. Mice were treated with herbal extracts for 7 days before exposing the animals to stress. Before each stressor presentation, the mice were treated with each herbal extract. Reduced locomotor activity and the percentage of time spent in the open arms of an elevated plus-maze under stress were recovered by treatment with the extract containing equal amounts of S. chinensis and S. baicalensis (CB11) at 200 and 400 mg/kg (p < 0.05). The effects of CB11 were greater than the effects of S. chinensis or S. baicalensis alone. CB11 treatment (100, 200 and 400 mg/kg) significantly reduced serum corticosterone levels (p < 0.05). Spleen size and the serum interleukin-2 level decreases induced by stress were prevented by CB11 (200 mg/kg) (p < 0.05). Taken together, these results suggest that S. chinensis and S. baicalensis in equal amounts could be used to treat stress disorders, in part, by preventing corticosterone and IL-2 level changes and ameliorating stress-related behavior parameters.
Phytotherapy Research 01/2008; 21(12):1187-92. · 2.09 Impact Factor
