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Stephen D Hall - One of the best experts on this subject based on the ideXlab platform.
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the effect of short and long term administration of Verapamil on the disposition of cytochrome p450 3a and p glycoprotein substrates
Clinical Pharmacology & Therapeutics, 2006Co-Authors: Girum L Lemma, Zaiqi Wang, Mitchell A Hamman, Narjis A Zaheer, Christopher J Gorski, Stephen D HallAbstract:Background Verapamil has the capability to inhibit and induce cytochrome P450 (CYP) 3A and P-glycoprotein (P-gp), but the relative extent and time course of these events in vivo are unclear. The effect of Verapamil on CYP3A and P-gp activity was determined by examining its effect on its own disposition and on the disposition of fexofenadine, respectively. Methods Twelve healthy volunteers received 60 mg fexofenadine alone or after administration of 240 mg Verapamil for 1, 10, and 38 days. The concentrations of Verapamil and norVerapamil, as well as their enantiomers, were quantified in serum by chiral HPLC. The concentrations of fexofenadine and its metabolite, azacyclonol, were quantified in serum and urine by liquid chromatography–mass spectrometry. Results The mean ± SD maximum serum concentration (Cmax) and the area under the serum concentration–time curve of S-Verapamil increased significantly on days 10 (40 ± 21 ng/mL [P = .00044] and 433 ± 316 ng·h·mL−1 [P = .00047], respectively) and 38 (42 ± 27 ng/mL [P = .019] and 433 ± 256 ng·h·mL−1 [P = .0081], respectively) compared with day 1 (21 ± 12 ng/mL and 222 ± 156 ng·h·mL−1, respectively). The oral clearance (CLoral) of S-Verapamil decreased significantly from 702 ± 304 L/h on day 1 to 377 ± 210 L/h on day 10 (P = .0029) and 449 ± 419 L/h on day 38 (P = .05). Similar trends were observed for the Cmax and area under the serum concentration–time curve of R-Verapamil and R- and S-norVerapamil. All subjects showed a significant decrease in the CLoral of fexofenadine after a single dose (98 ± 54 L/h, P = .00105) and 10-day dosing (102 ± 40 L/h, P = .0011) of Verapamil compared with the control value (156 ± 69 L/h). The Cmax of fexofenadine was significantly increased by a single dose (165 ± 42 ng/mL, P = .0005) and 10-day dosing (148 ± 39 ng/mL, P = .0008) of Verapamil compared with the control value (114 ± 45 ng/mL). No significant difference in fexofenadine Cmax (P = .37) and CLoral (P = .43) was observed between the control values and values at 38 days of Verapamil treatment. Conclusion Verapamil inhibited CYP3A activity, with a maximum effect occurring within 10 days. Short-term administration of Verapamil caused net inhibition of intestinal P-gp, whereas long-term administration of Verapamil induced P-gp activity. Clinical Pharmacology & Therapeutics (2006) 79, 218–230; doi: 10.1016/j.clpt.2005.11.001
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prediction of cytochrome p450 3a inhibition by Verapamil enantiomers and their metabolites
Drug Metabolism and Disposition, 2004Co-Authors: Y Wang, David R Jones, Stephen D HallAbstract:Verapamil inhibition of CYP3A activity results in many drug-drug interactions with CYP3A substrates, but the mechanism of inhibition is unclear. The present study showed that Verapamil enantiomers and their major metabolites [norVerapamil and N- desalkylVerapamil (D617)] inhibited CYP3A in a time- and concentration-dependent manner by using pooled human liver microsomes and the cDNA-expressed CYP3A4 (+b5). The values of the inactivation kinetic parameters k inact and K I obtained with the cDNA-expressed CYP3A4 (+b5) were 0.39 min-1 and 6.46 μM for R -Verapamil, 0.64 min-1 and 2.97 μM for S -Verapamil, 1.12 min-1 and 5.89 μM for (±)-norVerapamil, and 0.07 min-1 and 7.93 μM for D617. Based on the ratio of k inact and K I, the inactivation potency of Verapamil enantiomers and their metabolites was in the following order: S -norVerapamil > S -Verapamil > R -norVerapamil > R -Verapamil > D617. Using dual beam spectrophotometry, we confirmed that metabolic intermediate complex formation with CYP3A was the mechanism of inactivation for all compounds. The in vitro unbound fraction was 0.84 for S -Verapamil, 0.68 for R -Verapamil, and 0.84 for (±)-norVerapamil. A mechanism-based pharmacokinetic model predicted that the oral area under the curve (AUC) of a CYP3A substrate that is eliminated completely ( f m = 1) by the hepatic CYP3A increased 1.6- to 2.2-fold after repeated oral administration of Verapamil. For midazolam ( f m = 0.9), a drug that undergoes extensive intestinal wall metabolism, the predicted increase in oral AUC was 3.2- to 4.5-fold. The predicted results correlate well with the in vivo drug interaction data, suggesting that the model is suitable for predicting drug interactions by mechanism-based inhibitors.
Eric J F Franssen - One of the best experts on this subject based on the ideXlab platform.
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evaluation of tracer kinetic models for quantification of p glycoprotein function using r 11c Verapamil and pet
Journal of Cerebral Blood Flow and Metabolism, 2007Co-Authors: Mark Lubberink, Gert Luurtsema, Albert D Windhorst, Eric J F Franssen, Bart N M Van Berckel, Ronald Boellaard, Rolf Toornvliet, Adriaan A LammertsmaAbstract:Diminished P-glycoprotein (P-gp)-mediated transport across the blood-brain barrier may play an important role in several neurodegenerative disorders. In previous studies, a racemic mixture of (R)-[(11)C]Verapamil and (S)-[(11)C]Verapamil has been used as tracer for assessing P-gp function using positron emission tomography (PET). Quantification, however, is compromised by potential differences in kinetics between these two isomers. The aim of the present study was to evaluate the kinetics of pure (R)-[(11)C]Verapamil in humans and to develop a tracer kinetic model for the analysis of P-gp-mediated transport of (R)-[(11)C]Verapamil, including the putative contribution of its radioactive metabolites. Dynamic (R)-[(11)C]Verapamil PET scans of 10 male volunteers were analysed with various single- or two-tissue compartment models, with separate compartments for N-dealkylated and N-demethylated metabolites, assuming that either (R)-[(11)C]Verapamil alone or (R)-[(11)C]Verapamil and any combination of metabolites cross the BBB. In addition, six of the subjects underwent two (R)-[(11)C]Verapamil scans to evaluate test-retest reliability. One hour after injection, 50% of total plasma radioactivity consisted of labelled metabolites. Most models fitted the data well and the analysis did not point to a definite 'best' model, with differences in optimal model between subjects. The lowest mean test-retest variability (2.9%) was found for a single-tissue model without any metabolite correction. Models with separate metabolite compartments lead to high test-retest variability. Assuming that differences in kinetics of (R)-[(11)C]Verapamil and N-dealkylated metabolites are small, a one input, one-tissue model with correction for N-demethylated metabolites only leads to a good compromise between fit quality and test-retest variability.
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evaluation of r 11c Verapamil as pet tracer of p glycoprotein function in the blood brain barrier kinetics and metabolism in the rat
Nuclear Medicine and Biology, 2005Co-Authors: Gert Luurtsema, Carla F M Molthoff, Robert C Schuit, Albert D Windhorst, Adriaan A Lammertsma, Eric J F FranssenAbstract:There is evidence that P-glycoprotein (P-gp) in the blood-brain barrier (BBB) may be involved in the aetiology of neurological disorders. For quantification of P-gp function in vivo, (R)-[11C]Verapamil can be used as a positron emission tomography (PET) tracer, provided that a mathematical model describing kinetics of uptake and clearance of Verapamil is available. To develop and validate such a model, the kinetic profile and metabolism of (R)-[11C]Verapamil have to be known. The aim of this study was to investigate the presence of labeled metabolites of [11C]Verapamil in the plasma and (brain) tissue of Wistar rats. For this purpose, extraction and high-performance liquid chromatography (HPLC) methods were developed. The radioactive metabolites of (R)-[11C]Verapamil in the liver were N-dealkylated compounds, O-demethylated compounds and a polar fraction formed from N-demethylation products of (R)-[11C]Verapamil. Apart from this [11C] polar fraction, other radioactive metabolites of [11C]Verapamil were not detected in the brain tissue. Thirty minutes after injection, unmetabolized (R)-[11C]Verapamil accounted for 47% of radioactivity in the plasma and 69% in the brain. Sixty minutes after injection, unmetabolized (R)-[11C] Verapamil was 27% and 48% in the plasma and the brain, respectively.
Jos H Beijnen - One of the best experts on this subject based on the ideXlab platform.
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p glycoprotein system as a determinant of drug interactions the case of digoxin Verapamil
Pharmacological Research, 1999Co-Authors: Miranda Verschraagen, C H W Koks, Jan H M Schellens, Jos H BeijnenAbstract:Digoxin, which has a very narrow therapeutic window, is one of the most commonly prescribed drugs in the treatment of congestive heart failure. In some cases of atrial fibrillation digoxin is used in combination with Verapamil. Verapamil can increase the plasma concentration of digoxin up to 60-90%. So far the precise mechanism of this pharmacokinetic drug-drug interaction is not known. Many studies suggest that Verapamil reduces the renal clearance of digoxin. The energy-dependent membrane-bound transport enzyme, P-glycoprotein, may also be involved. Reports from oncology research show that Verapamil can interact with P-glycoprotein as a modulator. Also taking into account that digoxin, like many anticancer drugs, is a substrate for P-glycoprotein, it is likely that P-glycoprotein modulation accounts for the digoxin-Verapamil interaction. Current knowledge suggest that the non-competitive digoxin-Verapamil interaction is due to inhibition of P-glycoprotein activity by Verapamil resulting in a decreased renal tubular elimination of digoxin.
Gert Luurtsema - One of the best experts on this subject based on the ideXlab platform.
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evaluation of tracer kinetic models for quantification of p glycoprotein function using r 11c Verapamil and pet
Journal of Cerebral Blood Flow and Metabolism, 2007Co-Authors: Mark Lubberink, Gert Luurtsema, Albert D Windhorst, Eric J F Franssen, Bart N M Van Berckel, Ronald Boellaard, Rolf Toornvliet, Adriaan A LammertsmaAbstract:Diminished P-glycoprotein (P-gp)-mediated transport across the blood-brain barrier may play an important role in several neurodegenerative disorders. In previous studies, a racemic mixture of (R)-[(11)C]Verapamil and (S)-[(11)C]Verapamil has been used as tracer for assessing P-gp function using positron emission tomography (PET). Quantification, however, is compromised by potential differences in kinetics between these two isomers. The aim of the present study was to evaluate the kinetics of pure (R)-[(11)C]Verapamil in humans and to develop a tracer kinetic model for the analysis of P-gp-mediated transport of (R)-[(11)C]Verapamil, including the putative contribution of its radioactive metabolites. Dynamic (R)-[(11)C]Verapamil PET scans of 10 male volunteers were analysed with various single- or two-tissue compartment models, with separate compartments for N-dealkylated and N-demethylated metabolites, assuming that either (R)-[(11)C]Verapamil alone or (R)-[(11)C]Verapamil and any combination of metabolites cross the BBB. In addition, six of the subjects underwent two (R)-[(11)C]Verapamil scans to evaluate test-retest reliability. One hour after injection, 50% of total plasma radioactivity consisted of labelled metabolites. Most models fitted the data well and the analysis did not point to a definite 'best' model, with differences in optimal model between subjects. The lowest mean test-retest variability (2.9%) was found for a single-tissue model without any metabolite correction. Models with separate metabolite compartments lead to high test-retest variability. Assuming that differences in kinetics of (R)-[(11)C]Verapamil and N-dealkylated metabolites are small, a one input, one-tissue model with correction for N-demethylated metabolites only leads to a good compromise between fit quality and test-retest variability.
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evaluation of r 11c Verapamil as pet tracer of p glycoprotein function in the blood brain barrier kinetics and metabolism in the rat
Nuclear Medicine and Biology, 2005Co-Authors: Gert Luurtsema, Carla F M Molthoff, Robert C Schuit, Albert D Windhorst, Adriaan A Lammertsma, Eric J F FranssenAbstract:There is evidence that P-glycoprotein (P-gp) in the blood-brain barrier (BBB) may be involved in the aetiology of neurological disorders. For quantification of P-gp function in vivo, (R)-[11C]Verapamil can be used as a positron emission tomography (PET) tracer, provided that a mathematical model describing kinetics of uptake and clearance of Verapamil is available. To develop and validate such a model, the kinetic profile and metabolism of (R)-[11C]Verapamil have to be known. The aim of this study was to investigate the presence of labeled metabolites of [11C]Verapamil in the plasma and (brain) tissue of Wistar rats. For this purpose, extraction and high-performance liquid chromatography (HPLC) methods were developed. The radioactive metabolites of (R)-[11C]Verapamil in the liver were N-dealkylated compounds, O-demethylated compounds and a polar fraction formed from N-demethylation products of (R)-[11C]Verapamil. Apart from this [11C] polar fraction, other radioactive metabolites of [11C]Verapamil were not detected in the brain tissue. Thirty minutes after injection, unmetabolized (R)-[11C]Verapamil accounted for 47% of radioactivity in the plasma and 69% in the brain. Sixty minutes after injection, unmetabolized (R)-[11C] Verapamil was 27% and 48% in the plasma and the brain, respectively.
Adriaan A Lammertsma - One of the best experts on this subject based on the ideXlab platform.
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evaluation of tracer kinetic models for quantification of p glycoprotein function using r 11c Verapamil and pet
Journal of Cerebral Blood Flow and Metabolism, 2007Co-Authors: Mark Lubberink, Gert Luurtsema, Albert D Windhorst, Eric J F Franssen, Bart N M Van Berckel, Ronald Boellaard, Rolf Toornvliet, Adriaan A LammertsmaAbstract:Diminished P-glycoprotein (P-gp)-mediated transport across the blood-brain barrier may play an important role in several neurodegenerative disorders. In previous studies, a racemic mixture of (R)-[(11)C]Verapamil and (S)-[(11)C]Verapamil has been used as tracer for assessing P-gp function using positron emission tomography (PET). Quantification, however, is compromised by potential differences in kinetics between these two isomers. The aim of the present study was to evaluate the kinetics of pure (R)-[(11)C]Verapamil in humans and to develop a tracer kinetic model for the analysis of P-gp-mediated transport of (R)-[(11)C]Verapamil, including the putative contribution of its radioactive metabolites. Dynamic (R)-[(11)C]Verapamil PET scans of 10 male volunteers were analysed with various single- or two-tissue compartment models, with separate compartments for N-dealkylated and N-demethylated metabolites, assuming that either (R)-[(11)C]Verapamil alone or (R)-[(11)C]Verapamil and any combination of metabolites cross the BBB. In addition, six of the subjects underwent two (R)-[(11)C]Verapamil scans to evaluate test-retest reliability. One hour after injection, 50% of total plasma radioactivity consisted of labelled metabolites. Most models fitted the data well and the analysis did not point to a definite 'best' model, with differences in optimal model between subjects. The lowest mean test-retest variability (2.9%) was found for a single-tissue model without any metabolite correction. Models with separate metabolite compartments lead to high test-retest variability. Assuming that differences in kinetics of (R)-[(11)C]Verapamil and N-dealkylated metabolites are small, a one input, one-tissue model with correction for N-demethylated metabolites only leads to a good compromise between fit quality and test-retest variability.
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evaluation of r 11c Verapamil as pet tracer of p glycoprotein function in the blood brain barrier kinetics and metabolism in the rat
Nuclear Medicine and Biology, 2005Co-Authors: Gert Luurtsema, Carla F M Molthoff, Robert C Schuit, Albert D Windhorst, Adriaan A Lammertsma, Eric J F FranssenAbstract:There is evidence that P-glycoprotein (P-gp) in the blood-brain barrier (BBB) may be involved in the aetiology of neurological disorders. For quantification of P-gp function in vivo, (R)-[11C]Verapamil can be used as a positron emission tomography (PET) tracer, provided that a mathematical model describing kinetics of uptake and clearance of Verapamil is available. To develop and validate such a model, the kinetic profile and metabolism of (R)-[11C]Verapamil have to be known. The aim of this study was to investigate the presence of labeled metabolites of [11C]Verapamil in the plasma and (brain) tissue of Wistar rats. For this purpose, extraction and high-performance liquid chromatography (HPLC) methods were developed. The radioactive metabolites of (R)-[11C]Verapamil in the liver were N-dealkylated compounds, O-demethylated compounds and a polar fraction formed from N-demethylation products of (R)-[11C]Verapamil. Apart from this [11C] polar fraction, other radioactive metabolites of [11C]Verapamil were not detected in the brain tissue. Thirty minutes after injection, unmetabolized (R)-[11C]Verapamil accounted for 47% of radioactivity in the plasma and 69% in the brain. Sixty minutes after injection, unmetabolized (R)-[11C] Verapamil was 27% and 48% in the plasma and the brain, respectively.
