The Experts below are selected from a list of 1041 Experts worldwide ranked by ideXlab platform
Oliver Langer - One of the best experts on this subject based on the ideXlab platform.
-
Pharmacokinetics of the P-gp Inhibitor Tariquidar in Rats After Intravenous, Oral, and Intraperitoneal Administration.
European journal of drug metabolism and pharmacokinetics, 2018Co-Authors: Peter Matzneller, Alexandra Maier-salamon, Oliver Langer, Martin Bauer, Walter Jäger, Markus Zeitlinger, Manuel Kussmann, Sabine Eberl, Wolfgang PoepplAbstract:Background and objective P-glycoprotein (P-gp), a transmembrane transporter expressed at the blood–brain barrier, restricts the distribution of diverse central nervous system-targeted drugs from blood into brain, reducing their therapeutic efficacy. The third-generation P-gp inhibitor Tariquidar (XR9576) was shown to enhance brain distribution of P-gp substrate drugs in humans. Oral bioavailability of Tariquidar was found to be low in humans requiring the compound to be administered intravenously, which hinders a broader clinical use. The objective of the present study was to investigate the plasma pharmacokinetics of Tariquidar in rats after single intravenous, oral, and intraperitoneal administration.
-
pharmacokinetics of the p gp inhibitor Tariquidar in rats after intravenous oral and intraperitoneal administration
European Journal of Drug Metabolism and Pharmacokinetics, 2018Co-Authors: Peter Matzneller, Oliver Langer, Martin Bauer, Walter Jäger, Markus Zeitlinger, Manuel Kussmann, Sabine Eberl, Alexandra Maiersalamon, Wolfgang PoepplAbstract:P-glycoprotein (P-gp), a transmembrane transporter expressed at the blood–brain barrier, restricts the distribution of diverse central nervous system-targeted drugs from blood into brain, reducing their therapeutic efficacy. The third-generation P-gp inhibitor Tariquidar (XR9576) was shown to enhance brain distribution of P-gp substrate drugs in humans. Oral bioavailability of Tariquidar was found to be low in humans requiring the compound to be administered intravenously, which hinders a broader clinical use. The objective of the present study was to investigate the plasma pharmacokinetics of Tariquidar in rats after single intravenous, oral, and intraperitoneal administration. Two different Tariquidar formulations (A and B) were used, both at a dosage of 15 mg/kg, respectively. Formulation A was a solution and formulation B was a microemulsion which was previously shown to improve the oral bioavailability of the structurally related P-gp inhibitor elacridar in mice. In contrast to human data, the present study found a high bioavailability of Tariquidar in rats after oral dosing. Oral bioavailability was significantly higher (p = 0.032) for formulation B (86.3%) than for formulation A (71.6%). After intraperitoneal dosing bioavailability was 91.4% for formulation A and 99.6% for formulation B. The present findings extend the available information on Tariquidar and provide a basis for future studies involving oral administration of this compound.
-
A Prediction Method for P-glycoprotein–Mediated Drug–Drug Interactions at the Human Blood–Brain Barrier From Blood Concentration–Time Profiles, Validated With PET Data
Journal of pharmaceutical sciences, 2017Co-Authors: Akihiro Matsuda, Rudolf Karch, Martin Bauer, Markus Zeitlinger, Alexander Traxl, Oliver LangerAbstract:Abstract The purpose of this study was to establish physiologically based pharmacokinetic models to predict in humans the brain concentration–time profiles and P-glycoprotein (Pgp)–mediated brain drug–drug interactions between the model Pgp substrate ( R )-[ 11 C]verapamil (VPM), the model dual Pgp/breast cancer resistance protein (BCRP) substrate [ 11 C]Tariquidar (TQD), and the Pgp inhibitor Tariquidar. The model predictions were validated with results from positron emission tomography studies in humans. Using these physiologically based pharmacokinetic models, the differences between predicted and observed areas under the concentration–time curves (AUC) of VPM and TQD in the brain were within a 1.2-fold and 2.5-fold range, respectively. Also, brain AUC increases of VPM and TQD after Pgp inhibitor administration were predicted with 2.5-fold accuracy when in vitro inhibition constant or half-maximum inhibitory concentration values of Tariquidar were used. The predicted rank order of the magnitude of AUC increases reflected the results of the clinical positron emission tomography studies. Our results suggest that the established models can predict brain exposure from the respective blood concentration–time profiles and rank the magnitude of the Pgp-mediated brain drug–drug interaction potential for both Pgp and Pgp/BCRP substrates in humans.
-
whole body distribution and radiation dosimetry of 11c elacridar and 11c Tariquidar in humans
The Journal of Nuclear Medicine, 2016Co-Authors: Martin Bauer, Matthias Blaickner, Cecile Philippe, Marcus Hacker, Markus Zeitlinger, Wolfgang Wadsak, Oliver LangerAbstract:(11)C-elacridar and (11)C-Tariquidar are new PET tracers to assess the transport activity of P-glycoprotein (adenosine triphosphate-binding cassette subfamily B, member 1 [ABCB1]) and breast cancer resistance protein (adenosine triphosphate-binding cassette subfamily G, member 2 [ABCG2]). This study investigated the whole-body distribution and radiation dosimetry of both radiotracers in humans.Twelve healthy volunteers (6 women, 6 men) underwent whole-body PET/CT imaging over the 90 min after injection of either (11)C-elacridar or (11)C-Tariquidar. Radiation doses were calculated with OLINDA/EXM software using adult reference phantoms.Biodistribution was consistent with a major elimination route of hepatobiliary excretion, which may be mediated by ABCB1 and ABCG2. High radioactivity uptake was seen in liver, followed by spleen and kidneys, whereas brain uptake was lowest. Effective doses were 3.41 ± 0.06 μSv/MBq for (11)C-elacidar and 3.62 ± 0.11 μSv/MBq for (11)C-Tariquidar.Our data indicate that both (11)C-elacridar and (11)C-Tariquidar are safe radiotracers, for which an injected activity of 400 MBq corresponds to a total effective dose of approximately 1.5 mSv.
-
Whole-body Distribution and Radiation Dosimetry of 11C-Elacridar and 11C-Tariquidar in Humans
Journal of nuclear medicine : official publication Society of Nuclear Medicine, 2016Co-Authors: Martin Bauer, Matthias Blaickner, Cecile Philippe, Marcus Hacker, Markus Zeitlinger, Wolfgang Wadsak, Oliver LangerAbstract:11C-elacridar and 11C-Tariquidar are new PET tracers to assess the transport activity of P-glycoprotein (adenosine triphosphate–binding cassette subfamily B, member 1 [ABCB1]) and breast cancer resistance protein (adenosine triphosphate–binding cassette subfamily G, member 2 [ABCG2]). This study investigated the whole-body distribution and radiation dosimetry of both radiotracers in humans. Methods: Twelve healthy volunteers (6 women, 6 men) underwent whole-body PET/CT imaging over the 90 min after injection of either 11C-elacridar or 11C-Tariquidar. Radiation doses were calculated with OLINDA/EXM software using adult reference phantoms. Results: Biodistribution was consistent with a major elimination route of hepatobiliary excretion, which may be mediated by ABCB1 and ABCG2. High radioactivity uptake was seen in liver, followed by spleen and kidneys, whereas brain uptake was lowest. Effective doses were 3.41 ± 0.06 μSv/MBq for 11C-elacidar and 3.62 ± 0.11 μSv/MBq for 11C-Tariquidar. Conclusion: Our data indicate that both 11C-elacridar and 11C-Tariquidar are safe radiotracers, for which an injected activity of 400 MBq corresponds to a total effective dose of approximately 1.5 mSv.
Rudolf Karch - One of the best experts on this subject based on the ideXlab platform.
-
A Prediction Method for P-glycoprotein–Mediated Drug–Drug Interactions at the Human Blood–Brain Barrier From Blood Concentration–Time Profiles, Validated With PET Data
Journal of pharmaceutical sciences, 2017Co-Authors: Akihiro Matsuda, Rudolf Karch, Martin Bauer, Markus Zeitlinger, Alexander Traxl, Oliver LangerAbstract:Abstract The purpose of this study was to establish physiologically based pharmacokinetic models to predict in humans the brain concentration–time profiles and P-glycoprotein (Pgp)–mediated brain drug–drug interactions between the model Pgp substrate ( R )-[ 11 C]verapamil (VPM), the model dual Pgp/breast cancer resistance protein (BCRP) substrate [ 11 C]Tariquidar (TQD), and the Pgp inhibitor Tariquidar. The model predictions were validated with results from positron emission tomography studies in humans. Using these physiologically based pharmacokinetic models, the differences between predicted and observed areas under the concentration–time curves (AUC) of VPM and TQD in the brain were within a 1.2-fold and 2.5-fold range, respectively. Also, brain AUC increases of VPM and TQD after Pgp inhibitor administration were predicted with 2.5-fold accuracy when in vitro inhibition constant or half-maximum inhibitory concentration values of Tariquidar were used. The predicted rank order of the magnitude of AUC increases reflected the results of the clinical positron emission tomography studies. Our results suggest that the established models can predict brain exposure from the respective blood concentration–time profiles and rank the magnitude of the Pgp-mediated brain drug–drug interaction potential for both Pgp and Pgp/BCRP substrates in humans.
-
Interaction of 11C-Tariquidar and 11C-Elacridar with P-Glycoprotein and Breast Cancer Resistance Protein
2016Co-Authors: At The Human Blood–brain Barrier, Johann Stanek, Rudolf Karch, Martin Bauer, Helmuth Haslacher, Walter Jäger, Markus Zeitlinger, Markus Mitterhauser, Wolfgang Wadsak, Markus MullerAbstract:The adenosine triphosphate-binding cassette transporters P-glyco-protein (Pgp) and breast cancer resistance protein (BCRP) are 2 major gatekeepers at the blood–brain barrier (BBB) that restrict brain distribution of several clinically used drugs. In this study, we investigated the suitability of the radiolabeled Pgp/BCRP inhibitors 11C-Tariquidar and 11C-elacridar to assess Pgp density in the human brain with PET. Methods: Healthy subjects underwent a first PET scan of 120-min duration with either 11C-Tariquidar (n 5 6) or 11C-elacridar (n 5 5) followed by a second PET scan of 60-min duration with (R)-11C-verapamil. During scan 1 (at 60 min after radiotracer injection), unlabeled Tariquidar (3 mg/kg) was intravenously admin-istered. Data were analyzed using 1-tissue 2-rate-constant (1T2K) and 2-tissue 4-rate-constant (2T4K) compartment models and ei-ther metabolite-corrected or uncorrected arterial input functions. Results: After injection of 11C-Tariquidar or 11C-elacridar, the brai
-
OPEN BRIEF COMMUNICATION Approaching complete inhibition of P-glycoprotein at the human blood–brain barrier: an (R)-[11C]verapamil PET study
2016Co-Authors: Martin Bauer, Johann Stanek, Rudolf Karch, Kerstin Römermann, Marcus Hacker, Walter Jäger, Markus Zeitlinger, Wolfgang Wadsak, Ra Maier-salamon, Markus MullerAbstract:As P-glycoprotein (Pgp) inhibition at the blood–brain barrier (BBB) after administration of a single dose of Tariquidar is transient, we performed positron emission tomography (PET) scans with the Pgp substrate (R)-[11C]verapamil in five healthy volunteers during continuous intravenous Tariquidar infusion. Total distribution volume (VT) of (R)-[ 11C]verapamil in whole-brain gray matter increased by 273 ± 78 % relative to baseline scans without Tariquidar, which was higher than previously reported VT increases. During Tariquidar infusion whole-brain VT was comparable to VT in the pituitary gland, a region not protected by the BBB, which suggested that we were approaching complete Pgp inhibition at the human BBB
-
Pilot PET Study to Assess the Functional Interplay Between ABCB1 and ABCG2 at the Human Blood–Brain Barrier
Clinical Pharmacology & Therapeutics, 2016Co-Authors: Martin Bauer, Johann Stanek, Rudolf Karch, Beatrix Wulkersdorfer, Kerstin Römermann, Alexandra Maier-salamon, Christof Jungbauer, Cecile Philippe, Helmuth Haslacher, Wolfgang WadsakAbstract:ABCB1 and ABCG2 work together at the blood-brain barrier (BBB) to limit brain distribution of dual ABCB1/ABCG2 substrates. In this pilot study we used positron emission tomography (PET) to assess brain distribution of two model ABCB1/ABCG2 substrates ([(11) C]elacridar and [(11) C]Tariquidar) in healthy subjects without (c.421CC) or with (c.421CA) the ABCG2 single-nucleotide polymorphism (SNP) c.421C>A. Subjects underwent PET scans under conditions when ABCB1 and ABCG2 were functional and during ABCB1 inhibition with high-dose Tariquidar. In contrast to the ABCB1-selective substrate (R)-[(11) C]verapamil, [(11) C]elacridar and [(11) C]Tariquidar showed only moderate increases in brain distribution during ABCB1 inhibition. This provides evidence for a functional interplay between ABCB1 and ABCG2 at the human BBB and suggests that both ABCB1 and ABCG2 need to be inhibited to achieve substantial increases in brain distribution of dual ABCB1/ABCG2 substrates. During ABCB1 inhibition c.421CA subjects had significantly higher increases in [(11) C]Tariquidar brain distribution than c.421CC subjects, pointing to impaired cerebral ABCG2 function.
-
Pilot PET Study to Assess the Functional Interplay Between ABCB1 and ABCG2 at the Human Blood-Brain Barrier.
Clinical pharmacology and therapeutics, 2016Co-Authors: Martin Bauer, Johann Stanek, Rudolf Karch, Beatrix Wulkersdorfer, Kerstin Römermann, Alexandra Maier-salamon, Christof Jungbauer, Cecile Philippe, Helmuth Haslacher, Wolfgang WadsakAbstract:ABCB1 and ABCG2 work together at the blood-brain barrier (BBB) to limit brain distribution of dual ABCB1/ABCG2 substrates. In this pilot study we used positron emission tomography (PET) to assess brain distribution of two model ABCB1/ABCG2 substrates ([(11) C]elacridar and [(11) C]Tariquidar) in healthy subjects without (c.421CC) or with (c.421CA) the ABCG2 single-nucleotide polymorphism (SNP) c.421C>A. Subjects underwent PET scans under conditions when ABCB1 and ABCG2 were functional and during ABCB1 inhibition with high-dose Tariquidar. In contrast to the ABCB1-selective substrate (R)-[(11) C]verapamil, [(11) C]elacridar and [(11) C]Tariquidar showed only moderate increases in brain distribution during ABCB1 inhibition. This provides evidence for a functional interplay between ABCB1 and ABCG2 at the human BBB and suggests that both ABCB1 and ABCG2 need to be inhibited to achieve substantial increases in brain distribution of dual ABCB1/ABCG2 substrates. During ABCB1 inhibition c.421CA subjects had significantly higher increases in [(11) C]Tariquidar brain distribution than c.421CC subjects, pointing to impaired cerebral ABCG2 function.
Martin Bauer - One of the best experts on this subject based on the ideXlab platform.
-
pharmacokinetics of the p gp inhibitor Tariquidar in rats after intravenous oral and intraperitoneal administration
European Journal of Drug Metabolism and Pharmacokinetics, 2018Co-Authors: Peter Matzneller, Oliver Langer, Martin Bauer, Walter Jäger, Markus Zeitlinger, Manuel Kussmann, Sabine Eberl, Alexandra Maiersalamon, Wolfgang PoepplAbstract:P-glycoprotein (P-gp), a transmembrane transporter expressed at the blood–brain barrier, restricts the distribution of diverse central nervous system-targeted drugs from blood into brain, reducing their therapeutic efficacy. The third-generation P-gp inhibitor Tariquidar (XR9576) was shown to enhance brain distribution of P-gp substrate drugs in humans. Oral bioavailability of Tariquidar was found to be low in humans requiring the compound to be administered intravenously, which hinders a broader clinical use. The objective of the present study was to investigate the plasma pharmacokinetics of Tariquidar in rats after single intravenous, oral, and intraperitoneal administration. Two different Tariquidar formulations (A and B) were used, both at a dosage of 15 mg/kg, respectively. Formulation A was a solution and formulation B was a microemulsion which was previously shown to improve the oral bioavailability of the structurally related P-gp inhibitor elacridar in mice. In contrast to human data, the present study found a high bioavailability of Tariquidar in rats after oral dosing. Oral bioavailability was significantly higher (p = 0.032) for formulation B (86.3%) than for formulation A (71.6%). After intraperitoneal dosing bioavailability was 91.4% for formulation A and 99.6% for formulation B. The present findings extend the available information on Tariquidar and provide a basis for future studies involving oral administration of this compound.
-
Pharmacokinetics of the P-gp Inhibitor Tariquidar in Rats After Intravenous, Oral, and Intraperitoneal Administration.
European journal of drug metabolism and pharmacokinetics, 2018Co-Authors: Peter Matzneller, Alexandra Maier-salamon, Oliver Langer, Martin Bauer, Walter Jäger, Markus Zeitlinger, Manuel Kussmann, Sabine Eberl, Wolfgang PoepplAbstract:Background and objective P-glycoprotein (P-gp), a transmembrane transporter expressed at the blood–brain barrier, restricts the distribution of diverse central nervous system-targeted drugs from blood into brain, reducing their therapeutic efficacy. The third-generation P-gp inhibitor Tariquidar (XR9576) was shown to enhance brain distribution of P-gp substrate drugs in humans. Oral bioavailability of Tariquidar was found to be low in humans requiring the compound to be administered intravenously, which hinders a broader clinical use. The objective of the present study was to investigate the plasma pharmacokinetics of Tariquidar in rats after single intravenous, oral, and intraperitoneal administration.
-
A Prediction Method for P-glycoprotein–Mediated Drug–Drug Interactions at the Human Blood–Brain Barrier From Blood Concentration–Time Profiles, Validated With PET Data
Journal of pharmaceutical sciences, 2017Co-Authors: Akihiro Matsuda, Rudolf Karch, Martin Bauer, Markus Zeitlinger, Alexander Traxl, Oliver LangerAbstract:Abstract The purpose of this study was to establish physiologically based pharmacokinetic models to predict in humans the brain concentration–time profiles and P-glycoprotein (Pgp)–mediated brain drug–drug interactions between the model Pgp substrate ( R )-[ 11 C]verapamil (VPM), the model dual Pgp/breast cancer resistance protein (BCRP) substrate [ 11 C]Tariquidar (TQD), and the Pgp inhibitor Tariquidar. The model predictions were validated with results from positron emission tomography studies in humans. Using these physiologically based pharmacokinetic models, the differences between predicted and observed areas under the concentration–time curves (AUC) of VPM and TQD in the brain were within a 1.2-fold and 2.5-fold range, respectively. Also, brain AUC increases of VPM and TQD after Pgp inhibitor administration were predicted with 2.5-fold accuracy when in vitro inhibition constant or half-maximum inhibitory concentration values of Tariquidar were used. The predicted rank order of the magnitude of AUC increases reflected the results of the clinical positron emission tomography studies. Our results suggest that the established models can predict brain exposure from the respective blood concentration–time profiles and rank the magnitude of the Pgp-mediated brain drug–drug interaction potential for both Pgp and Pgp/BCRP substrates in humans.
-
Interaction of 11C-Tariquidar and 11C-Elacridar with P-Glycoprotein and Breast Cancer Resistance Protein
2016Co-Authors: At The Human Blood–brain Barrier, Johann Stanek, Rudolf Karch, Martin Bauer, Helmuth Haslacher, Walter Jäger, Markus Zeitlinger, Markus Mitterhauser, Wolfgang Wadsak, Markus MullerAbstract:The adenosine triphosphate-binding cassette transporters P-glyco-protein (Pgp) and breast cancer resistance protein (BCRP) are 2 major gatekeepers at the blood–brain barrier (BBB) that restrict brain distribution of several clinically used drugs. In this study, we investigated the suitability of the radiolabeled Pgp/BCRP inhibitors 11C-Tariquidar and 11C-elacridar to assess Pgp density in the human brain with PET. Methods: Healthy subjects underwent a first PET scan of 120-min duration with either 11C-Tariquidar (n 5 6) or 11C-elacridar (n 5 5) followed by a second PET scan of 60-min duration with (R)-11C-verapamil. During scan 1 (at 60 min after radiotracer injection), unlabeled Tariquidar (3 mg/kg) was intravenously admin-istered. Data were analyzed using 1-tissue 2-rate-constant (1T2K) and 2-tissue 4-rate-constant (2T4K) compartment models and ei-ther metabolite-corrected or uncorrected arterial input functions. Results: After injection of 11C-Tariquidar or 11C-elacridar, the brai
-
OPEN BRIEF COMMUNICATION Approaching complete inhibition of P-glycoprotein at the human blood–brain barrier: an (R)-[11C]verapamil PET study
2016Co-Authors: Martin Bauer, Johann Stanek, Rudolf Karch, Kerstin Römermann, Marcus Hacker, Walter Jäger, Markus Zeitlinger, Wolfgang Wadsak, Ra Maier-salamon, Markus MullerAbstract:As P-glycoprotein (Pgp) inhibition at the blood–brain barrier (BBB) after administration of a single dose of Tariquidar is transient, we performed positron emission tomography (PET) scans with the Pgp substrate (R)-[11C]verapamil in five healthy volunteers during continuous intravenous Tariquidar infusion. Total distribution volume (VT) of (R)-[ 11C]verapamil in whole-brain gray matter increased by 273 ± 78 % relative to baseline scans without Tariquidar, which was higher than previously reported VT increases. During Tariquidar infusion whole-brain VT was comparable to VT in the pituitary gland, a region not protected by the BBB, which suggested that we were approaching complete Pgp inhibition at the human BBB
Johann Stanek - One of the best experts on this subject based on the ideXlab platform.
-
Interaction of 11C-Tariquidar and 11C-Elacridar with P-Glycoprotein and Breast Cancer Resistance Protein
2016Co-Authors: At The Human Blood–brain Barrier, Johann Stanek, Rudolf Karch, Martin Bauer, Helmuth Haslacher, Walter Jäger, Markus Zeitlinger, Markus Mitterhauser, Wolfgang Wadsak, Markus MullerAbstract:The adenosine triphosphate-binding cassette transporters P-glyco-protein (Pgp) and breast cancer resistance protein (BCRP) are 2 major gatekeepers at the blood–brain barrier (BBB) that restrict brain distribution of several clinically used drugs. In this study, we investigated the suitability of the radiolabeled Pgp/BCRP inhibitors 11C-Tariquidar and 11C-elacridar to assess Pgp density in the human brain with PET. Methods: Healthy subjects underwent a first PET scan of 120-min duration with either 11C-Tariquidar (n 5 6) or 11C-elacridar (n 5 5) followed by a second PET scan of 60-min duration with (R)-11C-verapamil. During scan 1 (at 60 min after radiotracer injection), unlabeled Tariquidar (3 mg/kg) was intravenously admin-istered. Data were analyzed using 1-tissue 2-rate-constant (1T2K) and 2-tissue 4-rate-constant (2T4K) compartment models and ei-ther metabolite-corrected or uncorrected arterial input functions. Results: After injection of 11C-Tariquidar or 11C-elacridar, the brai
-
OPEN BRIEF COMMUNICATION Approaching complete inhibition of P-glycoprotein at the human blood–brain barrier: an (R)-[11C]verapamil PET study
2016Co-Authors: Martin Bauer, Johann Stanek, Rudolf Karch, Kerstin Römermann, Marcus Hacker, Walter Jäger, Markus Zeitlinger, Wolfgang Wadsak, Ra Maier-salamon, Markus MullerAbstract:As P-glycoprotein (Pgp) inhibition at the blood–brain barrier (BBB) after administration of a single dose of Tariquidar is transient, we performed positron emission tomography (PET) scans with the Pgp substrate (R)-[11C]verapamil in five healthy volunteers during continuous intravenous Tariquidar infusion. Total distribution volume (VT) of (R)-[ 11C]verapamil in whole-brain gray matter increased by 273 ± 78 % relative to baseline scans without Tariquidar, which was higher than previously reported VT increases. During Tariquidar infusion whole-brain VT was comparable to VT in the pituitary gland, a region not protected by the BBB, which suggested that we were approaching complete Pgp inhibition at the human BBB
-
Factors Governing P‑Glycoprotein-Mediated Drug−Drug Interactions at the Blood−Brain Barrier Measured with Positron Emission Tomography
2016Co-Authors: Thomas Wanek, Severin Mairinger, Johann Stanek, Claudia Kuntner, Michael Sauberer, Thomas Filip, Jens Pahnke, Florian Bauer, Er Traxl, Thomas ErkerAbstract:ABSTRACT: The adenosine triphosphate-binding cassette transporter P-glycoprotein (ABCB1/Abcb1a) restricts at the blood−brain barrier (BBB) brain distribution of many drugs. ABCB1 may be involved in drug−drug interactions (DDIs) at the BBB, which may lead to changes in brain distribution and central nervous system side effects of drugs. Positron emission tomography (PET) with the ABCB1 substrates (R)-[11C]-verapamil and [11C]-N-desmethyl-loperamide and the ABCB1 inhibitor Tariquidar has allowed direct comparison of ABCB1-mediated DDIs at the rodent and human BBB. In this work we evaluated different factors which could influence the magnitude of the interaction between Tariquidar and (R)-[11C]verapamil or [11C]-N-desmethyl-loperamide at the BBB and thereby contribute to previously observed species differences between rodents and humans. We performed in vitro transport experiments with [3H]verapamil and [3H]-N-desmethyl-loperamide in ABCB1 and Abcb1a overexpressing cell lines. Moreover we conducted in vivo PET experiments and biodistribution studies with (R)-[11C]verapamil and [11C]-N-desmethyl-loperamide in wild-type mice without and with Tariquidar pretreatment and in homozygous Abcb1a/1b(−/−) and heterozygous Abcb1a
-
Pilot PET Study to Assess the Functional Interplay Between ABCB1 and ABCG2 at the Human Blood–Brain Barrier
Clinical Pharmacology & Therapeutics, 2016Co-Authors: Martin Bauer, Johann Stanek, Rudolf Karch, Beatrix Wulkersdorfer, Kerstin Römermann, Alexandra Maier-salamon, Christof Jungbauer, Cecile Philippe, Helmuth Haslacher, Wolfgang WadsakAbstract:ABCB1 and ABCG2 work together at the blood-brain barrier (BBB) to limit brain distribution of dual ABCB1/ABCG2 substrates. In this pilot study we used positron emission tomography (PET) to assess brain distribution of two model ABCB1/ABCG2 substrates ([(11) C]elacridar and [(11) C]Tariquidar) in healthy subjects without (c.421CC) or with (c.421CA) the ABCG2 single-nucleotide polymorphism (SNP) c.421C>A. Subjects underwent PET scans under conditions when ABCB1 and ABCG2 were functional and during ABCB1 inhibition with high-dose Tariquidar. In contrast to the ABCB1-selective substrate (R)-[(11) C]verapamil, [(11) C]elacridar and [(11) C]Tariquidar showed only moderate increases in brain distribution during ABCB1 inhibition. This provides evidence for a functional interplay between ABCB1 and ABCG2 at the human BBB and suggests that both ABCB1 and ABCG2 need to be inhibited to achieve substantial increases in brain distribution of dual ABCB1/ABCG2 substrates. During ABCB1 inhibition c.421CA subjects had significantly higher increases in [(11) C]Tariquidar brain distribution than c.421CC subjects, pointing to impaired cerebral ABCG2 function.
-
Pilot PET Study to Assess the Functional Interplay Between ABCB1 and ABCG2 at the Human Blood-Brain Barrier.
Clinical pharmacology and therapeutics, 2016Co-Authors: Martin Bauer, Johann Stanek, Rudolf Karch, Beatrix Wulkersdorfer, Kerstin Römermann, Alexandra Maier-salamon, Christof Jungbauer, Cecile Philippe, Helmuth Haslacher, Wolfgang WadsakAbstract:ABCB1 and ABCG2 work together at the blood-brain barrier (BBB) to limit brain distribution of dual ABCB1/ABCG2 substrates. In this pilot study we used positron emission tomography (PET) to assess brain distribution of two model ABCB1/ABCG2 substrates ([(11) C]elacridar and [(11) C]Tariquidar) in healthy subjects without (c.421CC) or with (c.421CA) the ABCG2 single-nucleotide polymorphism (SNP) c.421C>A. Subjects underwent PET scans under conditions when ABCB1 and ABCG2 were functional and during ABCB1 inhibition with high-dose Tariquidar. In contrast to the ABCB1-selective substrate (R)-[(11) C]verapamil, [(11) C]elacridar and [(11) C]Tariquidar showed only moderate increases in brain distribution during ABCB1 inhibition. This provides evidence for a functional interplay between ABCB1 and ABCG2 at the human BBB and suggests that both ABCB1 and ABCG2 need to be inhibited to achieve substantial increases in brain distribution of dual ABCB1/ABCG2 substrates. During ABCB1 inhibition c.421CA subjects had significantly higher increases in [(11) C]Tariquidar brain distribution than c.421CC subjects, pointing to impaired cerebral ABCG2 function.
Markus Zeitlinger - One of the best experts on this subject based on the ideXlab platform.
-
Pharmacokinetics of the P-gp Inhibitor Tariquidar in Rats After Intravenous, Oral, and Intraperitoneal Administration.
European journal of drug metabolism and pharmacokinetics, 2018Co-Authors: Peter Matzneller, Alexandra Maier-salamon, Oliver Langer, Martin Bauer, Walter Jäger, Markus Zeitlinger, Manuel Kussmann, Sabine Eberl, Wolfgang PoepplAbstract:Background and objective P-glycoprotein (P-gp), a transmembrane transporter expressed at the blood–brain barrier, restricts the distribution of diverse central nervous system-targeted drugs from blood into brain, reducing their therapeutic efficacy. The third-generation P-gp inhibitor Tariquidar (XR9576) was shown to enhance brain distribution of P-gp substrate drugs in humans. Oral bioavailability of Tariquidar was found to be low in humans requiring the compound to be administered intravenously, which hinders a broader clinical use. The objective of the present study was to investigate the plasma pharmacokinetics of Tariquidar in rats after single intravenous, oral, and intraperitoneal administration.
-
pharmacokinetics of the p gp inhibitor Tariquidar in rats after intravenous oral and intraperitoneal administration
European Journal of Drug Metabolism and Pharmacokinetics, 2018Co-Authors: Peter Matzneller, Oliver Langer, Martin Bauer, Walter Jäger, Markus Zeitlinger, Manuel Kussmann, Sabine Eberl, Alexandra Maiersalamon, Wolfgang PoepplAbstract:P-glycoprotein (P-gp), a transmembrane transporter expressed at the blood–brain barrier, restricts the distribution of diverse central nervous system-targeted drugs from blood into brain, reducing their therapeutic efficacy. The third-generation P-gp inhibitor Tariquidar (XR9576) was shown to enhance brain distribution of P-gp substrate drugs in humans. Oral bioavailability of Tariquidar was found to be low in humans requiring the compound to be administered intravenously, which hinders a broader clinical use. The objective of the present study was to investigate the plasma pharmacokinetics of Tariquidar in rats after single intravenous, oral, and intraperitoneal administration. Two different Tariquidar formulations (A and B) were used, both at a dosage of 15 mg/kg, respectively. Formulation A was a solution and formulation B was a microemulsion which was previously shown to improve the oral bioavailability of the structurally related P-gp inhibitor elacridar in mice. In contrast to human data, the present study found a high bioavailability of Tariquidar in rats after oral dosing. Oral bioavailability was significantly higher (p = 0.032) for formulation B (86.3%) than for formulation A (71.6%). After intraperitoneal dosing bioavailability was 91.4% for formulation A and 99.6% for formulation B. The present findings extend the available information on Tariquidar and provide a basis for future studies involving oral administration of this compound.
-
A Prediction Method for P-glycoprotein–Mediated Drug–Drug Interactions at the Human Blood–Brain Barrier From Blood Concentration–Time Profiles, Validated With PET Data
Journal of pharmaceutical sciences, 2017Co-Authors: Akihiro Matsuda, Rudolf Karch, Martin Bauer, Markus Zeitlinger, Alexander Traxl, Oliver LangerAbstract:Abstract The purpose of this study was to establish physiologically based pharmacokinetic models to predict in humans the brain concentration–time profiles and P-glycoprotein (Pgp)–mediated brain drug–drug interactions between the model Pgp substrate ( R )-[ 11 C]verapamil (VPM), the model dual Pgp/breast cancer resistance protein (BCRP) substrate [ 11 C]Tariquidar (TQD), and the Pgp inhibitor Tariquidar. The model predictions were validated with results from positron emission tomography studies in humans. Using these physiologically based pharmacokinetic models, the differences between predicted and observed areas under the concentration–time curves (AUC) of VPM and TQD in the brain were within a 1.2-fold and 2.5-fold range, respectively. Also, brain AUC increases of VPM and TQD after Pgp inhibitor administration were predicted with 2.5-fold accuracy when in vitro inhibition constant or half-maximum inhibitory concentration values of Tariquidar were used. The predicted rank order of the magnitude of AUC increases reflected the results of the clinical positron emission tomography studies. Our results suggest that the established models can predict brain exposure from the respective blood concentration–time profiles and rank the magnitude of the Pgp-mediated brain drug–drug interaction potential for both Pgp and Pgp/BCRP substrates in humans.
-
Interaction of 11C-Tariquidar and 11C-Elacridar with P-Glycoprotein and Breast Cancer Resistance Protein
2016Co-Authors: At The Human Blood–brain Barrier, Johann Stanek, Rudolf Karch, Martin Bauer, Helmuth Haslacher, Walter Jäger, Markus Zeitlinger, Markus Mitterhauser, Wolfgang Wadsak, Markus MullerAbstract:The adenosine triphosphate-binding cassette transporters P-glyco-protein (Pgp) and breast cancer resistance protein (BCRP) are 2 major gatekeepers at the blood–brain barrier (BBB) that restrict brain distribution of several clinically used drugs. In this study, we investigated the suitability of the radiolabeled Pgp/BCRP inhibitors 11C-Tariquidar and 11C-elacridar to assess Pgp density in the human brain with PET. Methods: Healthy subjects underwent a first PET scan of 120-min duration with either 11C-Tariquidar (n 5 6) or 11C-elacridar (n 5 5) followed by a second PET scan of 60-min duration with (R)-11C-verapamil. During scan 1 (at 60 min after radiotracer injection), unlabeled Tariquidar (3 mg/kg) was intravenously admin-istered. Data were analyzed using 1-tissue 2-rate-constant (1T2K) and 2-tissue 4-rate-constant (2T4K) compartment models and ei-ther metabolite-corrected or uncorrected arterial input functions. Results: After injection of 11C-Tariquidar or 11C-elacridar, the brai
-
OPEN BRIEF COMMUNICATION Approaching complete inhibition of P-glycoprotein at the human blood–brain barrier: an (R)-[11C]verapamil PET study
2016Co-Authors: Martin Bauer, Johann Stanek, Rudolf Karch, Kerstin Römermann, Marcus Hacker, Walter Jäger, Markus Zeitlinger, Wolfgang Wadsak, Ra Maier-salamon, Markus MullerAbstract:As P-glycoprotein (Pgp) inhibition at the blood–brain barrier (BBB) after administration of a single dose of Tariquidar is transient, we performed positron emission tomography (PET) scans with the Pgp substrate (R)-[11C]verapamil in five healthy volunteers during continuous intravenous Tariquidar infusion. Total distribution volume (VT) of (R)-[ 11C]verapamil in whole-brain gray matter increased by 273 ± 78 % relative to baseline scans without Tariquidar, which was higher than previously reported VT increases. During Tariquidar infusion whole-brain VT was comparable to VT in the pituitary gland, a region not protected by the BBB, which suggested that we were approaching complete Pgp inhibition at the human BBB
