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Jun-shik Choi - One of the best experts on this subject based on the ideXlab platform.

  • Pharmacokinetic interaction between oral lovastatin and verapamil in healthy subjects: role of P-glycoprotein inhibition by lovastatin
    European Journal of Clinical Pharmacology, 2010
    Co-Authors: Dong-hyun Choi, Joong-hwa Chung, Jun-shik Choi
    Abstract:

    Background Lovastatin is an inhibitor of P-glycoprotein (P-gp) and is metabolized by the cytochrome P450 (CYP) 3A4 isoenzyme. Verapamil is a substrate of both P-gp and CYP3A4. It is therefore likely that lovastatin can alter the absorption and metabolism of verapamil. Methods The pharmacokinetic parameters of verapamil and one of its metabolites, Norverapamil, were compared in 14 healthy male Korean volunteers (age range 22–28 years) who had been administered verapamil (60 mg) orally in the presence or absence of oral lovastatin (20 mg). The design of the experiment was a standard 2 × 2 crossover model in random order. Results The pharmacokinetic parameters of verapamil were significantly altered by the co-administration of lovastatin compared to the control. The area under the plasma concentration–time curve $$ \left( {{\text{AU}}{{\text{C}}_{0 - \infty }}} \right) $$ and the peak plasma concentration of verapamil were significantly increased by 62.8 and 32.1%, respectively. Consequently, the relative bioavailability of verapamil was also significantly increased (by 76.5%). The $$ \left( {{\text{AU}}{{\text{C}}_{0 - \infty }}} \right) $$ of Norverapamil and the terminal half-life of verapamil did not significantly changed with lovastatin coadministration. The metabolite–parent ratio was significantly reduced (29.2%) in the presence of lovastatin. Conclusion Lovastatin increased the absorption of verapamil by inhibiting P-gp and inhibited the first-pass metabolism of verapamil by inhibiting CYP3A4 in the intestine and/or liver in humans.

  • Effects of lovastatin on the pharmacokinetics of verapamil and its active metabolite, Norverapamil in rats: Possible role of P-glycoprotein inhibition by lovastatin
    Archives of pharmacal research, 2009
    Co-Authors: Soon-pyo Hong, Dong-hyun Choi, Kyoung-sig Chang, Young-youp Koh, Jun-shik Choi
    Abstract:

    This study was to investigate the effect of lovastatin on the bioavailability or pharmacokinetics of verapamil and its major metabolite, Norverapamil, in rats. The pharmacokinetic parameters of verapamil and Norverapamil in rats were measured after the oral administration of verapamil (9 mg/kg) in the presence or absence of lovastatin (0.3 or 1.0 mg/kg). The pharmacokinetic parameters of verapamil were significantly altered by the presence of lovastatin compared to the control group (given verapamil alone). The presence of lovastatin significantly (p < 0.05, 0.3 mg/kg; p < 0.01, 1.0 mg/kg) increased the total area under the plasma concentration-time curve (AUC) of verapamil by 26.5–64.8%, and the peak plasma concentration (Cmax) of verapamil by 34.1–65.9%. Consequently, the relative bioavailability (R.B.) of verapamil was increased by 1.27- to 1.65-fold than that of the control group. However, there was not significant change in the time to reach the peak plasma concentration (Tmax) and the terminal half-life (t1/2) of verapamil in the presence of lovastatin. The AUC and Cmax of Norverapamil were significantly (p < 0.05) higher than those of presence of 1.0 mg/kg of lovastatin compared with the control group. However, there was no significant change in the metabolite-parent ratio (M.R.) of Norverapamil in the presence of lovastatin. The presence of lovastatin significantly enhanced the oral bioavailability of verapamil. The enhanced oral bioavailability of verapamil may be due to inhibition both of the CYP3A-mediated metabolism and the efflux pump P-glycoprotein (P-gp) in the intestine and/or in liver by the presence of lovastatin.

  • Effects of simvastatinon the pharmacokinetics of verapamil and its main metabolite, Norverapamil, in rats
    European Journal of Drug Metabolism and Pharmacokinetics, 2009
    Co-Authors: Dong-hyun Choi, Jun-shik Choi
    Abstract:

    The aim of this study was to investigate the effect of simvastatin on the pharmacokinetics of verapamil and its major metabolite, Norverapamil, in rats. The pharmacokinetic parameters of verapamil and Norverapamil in rats were determined after the oral administration of verapamil (9 mg/kg) in the presence or absence of simvastatin (0.3 and 1.0 mg/kg). The pharmacokinetics of verapamil were significantly altered by the coadministration of simvastatin compared with those in the control group (given verapamil alone). The area under the plasma concentration-time curve (AUC) and the peak plasma concentration (Cmax) of verapamil were significantly increased (P < 0.05 at 0.3 mg/kg;P < 0.01 at 1.0 mg/kg) by simvastatin. Consequently, the absolute bioavailability (A.B.) of verapamil with simvastatin (7.3 % at 0.3 mg/kg, 9.3 % at 1.0 mg/kg) were significantly higher than those in the control group (P < 0.05, 5.2 %). The AUC and Cmax of Norverapamil were not significantly increased in the rats coadministered with simvastatin compared with those in the control group. Moreover, the metabolite-parent ratio (M.R.) of Norverapamil were significantly decreased in rats coadministered with simvastatin. These results implied that simvastatin significantly enhanced the oral bioavailability of verapamil by inhibiting the CYP3A-mediated metabolism in small intestine or in the liver and P-glycoprotein (P-gp) efflux pump in small intestine. Therefor, concurrent use of verapamil and simvastatin should be monitored closely to potential drug interactions for safe therapy of cardiovascular diseases.

  • Effects of simvastatin on the pharmacokinetics of verapamil and its main metabolite, Norverapamil, in rats.
    European journal of drug metabolism and pharmacokinetics, 2009
    Co-Authors: Dong-hyun Choi, Jun-shik Choi
    Abstract:

    The aim of this study was to investigate the effect of simvastatin on the pharmacokinetics of verapamil and its major metabolite, Norverapamil, in rats. The pharmacokinetic parameters of verapamil and Norverapamil in rats were determined after the oral administration of verapamil (9 mg/kg) in the presence or absence of simvastatin (0.3 and 1.0 mg/kg). The pharmacokinetics of verapamil were significantly altered by the coadministration of simvastatin compared with those in the control group (given verapamil alone). The area under the plasma concentration-time curve (AUC) and the peak plasma concentration (Cmax) of verapamil were significantly increased (P < 0.05 at 0.3 mg/kg; P < 0.01 at 1.0 mg/kg) by simvastatin. Consequently, the absolute bioavailability (A.B.) of verapamil with simvastatin (7.3% at 0.3 mg/kg, 9.3% at 1.0 mg/kg) were significantly higher than those in the control group (P < 0.05, 5.2%). The AUC and Cmax of Norverapamil were not significantly increased in the rats coadministered with simvastatin compared with those in the control group. Moreover, the metabolite-parent ratio (M.R.) of Norverapamil were significantly decreased in rats coadministered with simvastatin. These results implied that simvastatin significantly enhanced the oral bioavailability of verapamil by inhibiting the CYP3A-mediated metabolism in small intestine or in the liver and P-glycoprotein (P-gp) efflux pump in small intestine. Therefore, concurrent use of verapamil and simvastatin should be monitored closely to potential drug interactions for safe therapy of cardiovascular diseases.

  • Effects of oral epigallocatechin gallate on the oral pharmacokinetics of verapamil in rats
    Biopharmaceutics & drug disposition, 2009
    Co-Authors: Joong-hwa Chung, Dong-hyun Choi, Jun-shik Choi
    Abstract:

    Verapamil is known to be a P-glycoprotein (P-gp) substrate and Norverapamil is formed via hepatic cytochrome P450 (CYP 3A) in the rat. Epigallocatechin gallate (EGCG), a flavonoid, was reported to be an inhibitor of both P-gp and CYP3A. Hence, it could be expected that EGCG could alter the pharmacokinetics of verapamil. In this study, 9 mg/kg verapamil was administered orally to Sprague-Dawley rats 30 min after the oral administration of 2 and 10 mg/kg of oral EGCG. Compared with the controls, the AUC values of both verapamil (74.3% and 111% increase for 2 and 10 mg/kg EGCG, respectively) and Norverapamil (51.5% and 87.2% increase for 2 and 10 mg/kg EGCG, respectively) were significantly greater in the presence of EGCG. However, compared with the controls, both the AUC and the relative bioavailability of verapamil were significantly (p

Ronald T Borchardt - One of the best experts on this subject based on the ideXlab platform.

  • absorption barriers in the rat intestinal mucosa 1 application of an in situ perfusion model to simultaneously assess drug permeation and metabolism
    Journal of Pharmaceutical Sciences, 2010
    Co-Authors: Daniel R Mudra, Ronald T Borchardt
    Abstract:

    Modulation of intestinal drug absorption barriers can have a profound impact on the bioavailability of orally administered compounds. With its commonality of use as an absorption model, it is valuable to assess the role of such barriers in the rat intestinal mucosa. In the present study, atenolol and verapamil were concomitantly delivered in the in situ perfused rat intestine in the presence or absence of inhibitors to simultaneously assess the function and modulation of passive diffusion barriers, cytochrome P450 (CYP)3A metabolism and P-glycoprotein (P-gp) efflux. A high performance liquid chromatography-tandem mass spectrometry method measured atenolol, verapamil and the CYP3A-mediated metabolite, Norverapamil, with linearity (r2 > 0.99), precision (CV ≤7.5%) and accuracy (±17%). Absorption of parent drug was independent of verapamil concentration; however the formation and disposition of Norverapamil were concentration-dependent and saturable. Norverapamil formation decreased (up to 80%) in the presence of CYP3A inhibitors and the fraction of Norverapamil observed in the plasma was increased (4.5- to 7.2-fold) in the presence of P-gp inhibitors. These results suggest that in this model of the rat intestinal mucosa, atenolol serves as a marker for diffusion barriers whereas Norverapamil formation and disposition are markers of CYP3A and P-gp, respectively. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:982–998, 2010

  • absorption barriers in the rat intestinal mucosa 2 application of physiologically based mathematical models to quantify mechanisms of drug permeation and metabolism
    Journal of Pharmaceutical Sciences, 2010
    Co-Authors: Daniel R Mudra, Ronald T Borchardt
    Abstract:

    The absorption of drug molecules is often investigated using in vitro or in situ models of the intestinal mucosa; however, few studies have quantified the kinetics that limit absorption. The objective of this study was to quantify kinetic rates of rat intestinal absorption, metabolism, and efflux using nonlinear mixed effects modeling. A multicompartment model accurately described the absorption and distribution of atenolol and verapamil as well as the metabolism of verapamil and distribution of the metabolite, Norverapamil. The accurate description of atenolol data required inclusion of an intermediate compartment in addition to paracellular clearance, whereas verapamil and Norverapamil were modeled in the absence of paracellular clearance. The absorption of verapamil was well characterized by linear kinetics, whereas the formation and distribution of Norverapamil were well characterized by Michaelis–Menten kinetics. The model identified EDTA as a modulator of physical barriers, ketoconazole as an inhibitor of cytochrome P450 3A and P-glycoprotein (P-gp), and PSC-833 and GF-120918 as specific P-gp inhibitors. These results demonstrate the utility of a physiologically based model to characterize (i) the drug distribution across the in situ perfused rat intestine and (ii) the effect of chemical modulators in this biological system. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:999–1015, 2010

Kurt C Kleinschmidt - One of the best experts on this subject based on the ideXlab platform.

Hans Lennernäs - One of the best experts on this subject based on the ideXlab platform.

  • Simultaneous quantification of the enantiomers of verapamil and its N-demethylated metabolite in human plasma using liquid chromatography-tandem mass spectrometry
    Journal of chromatography. B Analytical technologies in the biomedical and life sciences, 2004
    Co-Authors: Mikael Hedeland, Hans Lennernäs, Elisabeth Fredriksson, Ulf Bondesson
    Abstract:

    A stereoselective bioanalytical method for the simultaneous quantification of the enantiomers of verapamil and its active main metabolite Norverapamil in human plasma has been developed and validated. The samples were analysed by liquid chromatography-electrospray-tandem mass spectrometry (LC-ESI-MS/MS) in the Selected Reaction Monitoring (SRM) mode using a deuterated internal standard. The stationary phase used for the chiral separation was a Chiral-AGP. The enantiomers of verapamil were selectively detected from those of Norverapamil by the mass spectrometer due to different molecular masses, although there was a chromatographic co-elution. Thus, time-consuming procedures like achiral preseparation or chemical derivatisation could be avoided. Higher detection sensitivity than earlier published methods based on fluorescence detection was obtained, although a mobile phase of high water-content and high flow-rate was introduced into the electrospray interface (85% aqueous ammonium acetate pH 7.4 +15% acetonitrile at 0.6 ml/min). The enantiomers of verapamil and Norverapamil could be quantified at levels down to 50 pg and 60 pg/500 microl plasma sample, respectively, with R.S.D. in the range of 3.6-7.8%. The presented method was successfully applied to an in vivo intestinal absorption and bioavailability study in humans, using the Loc-I-Gut method.

  • Enantiomeric separation of verapamil and Norverapamil using Chiral-AGP® as the stationary phase
    Journal of pharmaceutical and biomedical analysis, 1999
    Co-Authors: Rikard Sandström, Hans Lennernäs, Kristina Öhlén, Anders Karlsson
    Abstract:

    Simultaneous enantiomeric separation of verapamil and its main metabolite Norverapamil was achieved using Chiral-AGP as the stationary phase. The optimized chromatographic system was obtained using statistical experimental design with partial least squares as regression method. The three variables studied were buffer pH, content of acetonitrile and column temperature. A high buffer pH favors enantioselectivity as well as the selectivity between (S)-verapamil and (R)-Norverapamil. The concentration of the organic modifier in the mobile phase was a compromise as a high content of acetonitrile decreased enantioselectivity but increased the selectivity mentioned above. Increased column temperature increased the separation between (S)-verapamil and (R)-Norverapamil with only a slight decrease in enantioresolution.

  • Repeated Oral Rifampicin Decreases the Jejunal Permeability of R/S-Verapamil in Rats
    Drug metabolism and disposition: the biological fate of chemicals, 1999
    Co-Authors: Rikard Sandström, Hans Lennernäs
    Abstract:

    The main purpose of this rat study was to investigate the effect of rifampicin on the effective permeability (P eff ) of R/S -verapamil in the rat jejunum. In addition the effect on metabolism of R/S -verapamil to R/S -Norverapamil was examined. In situ single-pass perfusions of the rat jejunum were performed in animals pretreated with oral rifampicin (250 mg/kg/day) or saline (control) over various time periods (1, 4, 7, and 14 days). The jejunal P eff of each of the enantiomers of verapamil and d-glucose was estimated. The appearance ratios of the CYP3A-formed metabolites R - and S -Norverapamil were also estimated in the outlet jejunal perfusate. The jejunal P eff of both R - and S -verapamil decreased as an effect of the oral pretreatment with rifampicin. The appearance of R - and S -Norverapamil in the jejunum was also affected by the oral pretreatment with rifampicin, with increasing concentrations of R/S -Norverapamil being evident after 14 days of rifampicin pretreatment. There was no stereoselectivity in either the P eff of R - and S -verapamil or the metabolic appearance of R - and S -Norverapamil. Treatment with oral rifampicin decreased the P eff of R/S -verapamil, which is in accordance with an induction of P-glycoprotein activity in the apical enterocyte membrane. The increase in appearance of R/S -Norverapamil in jejunum is in accordance with an induction of CYP3A metabolism in the rat.

  • Enantiomeric separation of verapamil and Norverapamil using Chiral-AGP (R) as the stationary phase
    1999
    Co-Authors: Rikard Sandström, Hans Lennernäs, Kristina Öhlén, Anders Karlsson
    Abstract:

    Enantiomeric separation of verapamil and Norverapamil using Chiral-AGP (R) as the stationary phase

  • The absence of stereoselective p-glycoprotein-mediated transport of R/S-verapamil across the rat jejunum
    Journal of Pharmacy and Pharmacology, 1998
    Co-Authors: Rikard Sandström, Anders Karlsson, Hans Lennernäs
    Abstract:

    We have studied the potential stereoselective transport and metabolism of R/S-verapamil in rat jejunum, in-situ. A regional single-pass perfusion of the rat jejunum was performed on 24 rats in six separate groups. The effective permeability (Peff) was assessed for three different concentrations of verapamil, 4, 40 and 400 mg L−1. The Peff of each enantiomer was also determined at 400 mg L−1 when chlorpromazine (10 mM) was added to the perfusion solution. Two other groups of rats received R/S-verapamil as an intravenous infusion and the intestinal secretion and metabolism were studied by simultaneously perfusing the jejunum with a control or with chlorpromazine (10 mM) added. The concentrations in the outlet perfusate of each enantiomer of verapamil and Norverapamil were assayed with HPLC. R/S-Verapamil is a high permeability drug in the proximal rat small intestine throughout the luminal concentration range studied and complete intestinal absorption was expected. There was an increase of Peff from 0.42 times 10−4 cm s−1 to 0.80 times 10−4 cm s−1 (P < 0.05) at concentrations from 4 to 400 mg L−1, respectively. The observed concentration-dependent jejunal Peff and fraction absorbed (P < 0.05) of R/S-verapamil is consistent with the saturation of an efflux mechanism. When chlorpromazine (a P-glycoprotein inhibitor/substrate) was added the jejunal Peff increased to 1.47 times 10−4 cm s−1. There was no difference between the Peff of the two enantiomers in any of these experiments. The efflux of R/S-Norverapamil into the rat jejunum was high after intravenous administration of R/S-verapamil, suggesting extensive metabolism in the enterocyte. In conclusion, both R/S-verapamil enantiomers are P-glycoprotein substrates, but there is no stereoselective transport of R/S-verapamil in the rat jejunum. The results also suggests that R/S-Norverapamil is formed inside the enterocytes.

Daniel R Mudra - One of the best experts on this subject based on the ideXlab platform.

  • absorption barriers in the rat intestinal mucosa 1 application of an in situ perfusion model to simultaneously assess drug permeation and metabolism
    Journal of Pharmaceutical Sciences, 2010
    Co-Authors: Daniel R Mudra, Ronald T Borchardt
    Abstract:

    Modulation of intestinal drug absorption barriers can have a profound impact on the bioavailability of orally administered compounds. With its commonality of use as an absorption model, it is valuable to assess the role of such barriers in the rat intestinal mucosa. In the present study, atenolol and verapamil were concomitantly delivered in the in situ perfused rat intestine in the presence or absence of inhibitors to simultaneously assess the function and modulation of passive diffusion barriers, cytochrome P450 (CYP)3A metabolism and P-glycoprotein (P-gp) efflux. A high performance liquid chromatography-tandem mass spectrometry method measured atenolol, verapamil and the CYP3A-mediated metabolite, Norverapamil, with linearity (r2 > 0.99), precision (CV ≤7.5%) and accuracy (±17%). Absorption of parent drug was independent of verapamil concentration; however the formation and disposition of Norverapamil were concentration-dependent and saturable. Norverapamil formation decreased (up to 80%) in the presence of CYP3A inhibitors and the fraction of Norverapamil observed in the plasma was increased (4.5- to 7.2-fold) in the presence of P-gp inhibitors. These results suggest that in this model of the rat intestinal mucosa, atenolol serves as a marker for diffusion barriers whereas Norverapamil formation and disposition are markers of CYP3A and P-gp, respectively. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:982–998, 2010

  • absorption barriers in the rat intestinal mucosa 2 application of physiologically based mathematical models to quantify mechanisms of drug permeation and metabolism
    Journal of Pharmaceutical Sciences, 2010
    Co-Authors: Daniel R Mudra, Ronald T Borchardt
    Abstract:

    The absorption of drug molecules is often investigated using in vitro or in situ models of the intestinal mucosa; however, few studies have quantified the kinetics that limit absorption. The objective of this study was to quantify kinetic rates of rat intestinal absorption, metabolism, and efflux using nonlinear mixed effects modeling. A multicompartment model accurately described the absorption and distribution of atenolol and verapamil as well as the metabolism of verapamil and distribution of the metabolite, Norverapamil. The accurate description of atenolol data required inclusion of an intermediate compartment in addition to paracellular clearance, whereas verapamil and Norverapamil were modeled in the absence of paracellular clearance. The absorption of verapamil was well characterized by linear kinetics, whereas the formation and distribution of Norverapamil were well characterized by Michaelis–Menten kinetics. The model identified EDTA as a modulator of physical barriers, ketoconazole as an inhibitor of cytochrome P450 3A and P-glycoprotein (P-gp), and PSC-833 and GF-120918 as specific P-gp inhibitors. These results demonstrate the utility of a physiologically based model to characterize (i) the drug distribution across the in situ perfused rat intestine and (ii) the effect of chemical modulators in this biological system. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:999–1015, 2010