"Tariquidar"

Pharmacokinetics of the P-gp Inhibitor Tariquidar in Rats After Intravenous, Oral, and Intraperitoneal Administration 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

Tariquidar Sensitizes Multiple Myeloma Cells to Proteasome Inhibitors via Reduction of Hypoxia-Induced P-gp-Mediated Drug Resistance Multiple myeloma (MM) presents a poor prognosis and high lethality of patients due to development of drug resistance. P-glycoprotein (P-gp), a drug-efflux transporter, is upregulated in MM patients post-chemotherapy and is involved in the development of drug marker, HIF-1α. Hypoxia increased P-gp protein expression and its efflux capabilities in MM cells in vitro using flow cytometry. We reported herein that hypoxia-mediated resistance to carfilzomib and bortezomib in MM cells is due to P-gp activity and was reversed by tariquidar, a P-gp inhibitor. These results suggest combining proteasome inhibitors with P-gp inhibition for future clinical studies.

Whole-Body Distribution and Radiation Dosimetry of 11C-Elacridar and 11C-Tariquidar in Humans. (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

3D-QSAR AND CONTOUR MAP ANALYSIS OF TARIQUIDAR ANALOGUES AS MULTIDRUG RESISTANCE PROTEIN-1 (MRP1) INHIBITORS One of the major obstacles to the successful chemotherapy towards several cancers is multidrug resistance of human cancer cells to anti-cancer drugs. An important contributor to multidrug resistance is the human multidrug resistance protein-1 transporter (MRP1), which is an efflux pump of the ABC (ATP binding cassette) superfamily. Thus, highly efficacious, third generation MRP1 inhibitors, like tariquidar analogues, are promising inhibitors of multidrug resistance and are under clinical trials. To maximize the efficacy of MRP1 inhibitors and to reduce systemic toxicity, it is important to limit the exposure of MRP1 inhibitors and anticancer drugs to normal tissues and to increase

Tariquidar Is an Inhibitor and Not a Substrate of Human and Mouse P-glycoprotein Since its development, tariquidar (TQR; XR9576; N-[2-[[4-[2-(6,7-Dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)ethyl]phenyl]carbamoyl]-4,5-dimethoxyphenyl]quinoline-3-carboxamide) has been widely regarded as one of the more potent inhibitors of P-glycoprotein (P-gp), an efflux transporter of the ATP-binding cassette (ABC

Increased permeability-glycoprotein inhibition at the human blood-brain barrier can be safely achieved by performing PET during peak plasma concentrations of tariquidar. The permeability-glycoprotein (P-gp) efflux transporter is densely expressed at the blood-brain barrier, and its resultant spare capacity requires substantial blockade to increase the uptake of avid substrates, blunting the ability of investigators to measure clinically meaningful alterations in P-gp function. This study, conducted in humans, examined 2 P-gp inhibitors (tariquidar, a known inhibitor, and disulfiram, a putative inhibitor) and 2 routes of administration (intravenous and oral) to maximally increase brain uptake of the avid and selective P-gp substrate (11)C-N-desmethyl-loperamide (dLop) while avoiding side

Pharmacokinetics of single ascending doses of the P-glycoprotein inhibitor tariquidar in healthy subjects. We assessed the pharmacokinetics (PK), tolerability and safety of tariquidar (TQD), a P-glycoprotein (Pgp) inhibitor, after intravenous administration of single ascending doses. Employed doses were up to 4-fold higher than in previous clinical trials in cancer patients and are capable

Interaction of 11C-tariquidar and 11C-elacridar with P-glycoprotein and breast cancer resistance protein at the human blood-brain barrier. The adenosine triphosphate-binding cassette transporters P-glycoprotein (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 (11)C-tariquidar and (11)C-elacridar to assess Pgp density in the human brain with PET. Healthy subjects underwent a first PET scan of 120-min duration with either (11)C-tariquidar (n = 6) or (11)C-elacridar (n = 5) followed by a second PET scan of 60-min duration with (R)-(11)C-verapamil. During scan 1 (at 60 min after

Tariquidar-ondansetron Combination in Neuropathic Pain Prospective, randomized, double-blind, placebo controlled, cross-over proof of concept study.To determine the pharmacokinetics and tolerability of co-administration of 5-HT3R antagonist ondansetron with a P-glycoprotein inhibitor tariquidar, in patients with neuropathic pain. The investigators hypothesize that co-administration of a 5-HT3 receptor antagonist ondansetron (single 16mg dose) with p-glycoprotein inhibitor tariquidar (single 4mg/kg dose) vs placebo in a cross-over prospective randomized study, will:Be tolerable in patients with neuropathic pain.Increase the cerebrospinal fluid (CSF) to plasma ratio of ondansetron after intravenous administration, compare to ondansetron aloneResult in a greater reduction in pain intensity than

(baseline) and with partial P-gp inhibition by tariquidar in wild-type, heterozygous and homozygous mice as models with controlled levels of cerebral P-gp expression. Brains were collected to quantify P-gp expression with immunohistochemistry. Brain uptake of [C]metoclopramide was expressed as the area under the brain time-activity curve (AUC) and compared with data previously obtained with ()-[C

probes to detect moderate changes in P-gp function at the living BBB. , the half-maximum inhibitory concentration (IC) of the potent P-gp inhibitor tariquidar in P-gp-overexpressing cells was significantly different using either [C]verapamil (44 nM), [C]-desmethyl-loperamide (19 nM) or [C]metoclopramide (4 nM) as substrate probes. PET imaging in rats showed that the half-maximum inhibition of P-gp -mediated efflux of [C]metoclopramide, achieved using 1 mg/kg tariquidar ( IC = 82 nM in plasma), increased brain exposure by 2.1-fold for [C]metoclopramide (p < 0.05, n = 4) and 2.4-fold for [C]verapamil (p < 0.05, n = 4), whereby cerebral uptake of the "avid" substrate [C]-desmethyl-loperamide was unaffected (p > 0.05, n = 4). This comparative study points to differences in the "vulnerability" to P-gp

was assessed by measuring its uptake in the brains of wild-type, Abcb1a/b, and Abcg2 mice at baseline and after administration of the ABCB1 inhibitor tariquidar (n = 5/group). Metabolism and biodistribution of [F]AVT-011 were also measured. To measure ABCB1 function in tumors, we performed PET experiments using both [F]AVT-011 and [F]FDG in mice bearing orthotopic breast tumors (n = 7-10/group) expressing clinically relevant levels of ABCB1. At baseline, brain uptake was highest in Abcb1a/b mice. After tariquidar administration, brain uptake increased 3-fold and 8-fold in wild-type and Abcg2 mice, respectively, but did not increase further in Abcb1a/b mice. At 30 min after injection, the radiotracer was > 90% in its parent form and had highest uptake in organs of the hepatobiliary system. Compared

CD30 expression and induction of ABCB1. BV resistance was reversed in vitro by tariquidar, but combination BV and tariquidar treatment only briefly slowed xenograft growth compared with BV alone. Combining BV with either crizotinib or ceritinib resulted in marked tumour shrinkage in both xenograft models, and resulted in prolonged tumour-free survival in the diagnosis compared with the relapse

with the third-generation P-gp inhibitor tariquidar (TQD) to evaluate P-gp function in individuals with drug-resistant epileptogenic developmental lesions. Twelve healthy controls (7 male, median age 45, range 35-55 years), and two patients with epileptogenic developmental lesions (2 male, aged 24 and 62 years) underwent VPM-PET scans before and 60 minutes after a 30-minute infusion of 2 and 3 mg/kg TQD

inhibition on the sensitivity of ACC cells to cytotoxic drugs were evaluated. MDR1 mRNA and P-gp expression were determined in human adrenal tissues and cell lines. H295R, HAC15 and SW13 cells were treated with mitotane, doxorubicin, etoposide, cisplatin and streptozotocin, with or without the P-gp inhibitors verapamil and tariquidar. Cell growth and surviving fraction of colonies were assessed. MDR1 mRNA and P-gp protein expression were lower in ACCs than in adrenocortical adenomas (P < 0.0001; P < 0.01, respectively). MDR1 and P-gp expression were positively correlated in ACC (P < 0.0001, ρ = 0.723). Mitotane, doxorubicin, cisplatin and etoposide dose dependently inhibited cell growth in H295R, HAC15 and SW13. Tariquidar, and in H295R also verapamil, increased the response of HAC15 and H295R

: a baseline scan and a second scan either with concurrent intravenous infusion of the ABCB1 inhibitor tariquidar (3.75 mg/min, = 5) or after oral intake of single ascending doses of erlotinib (300 mg, = 7; 650 mg, = 8; or 1,000 mg, = 2). : Although tariquidar administration had no effect on C-erlotinib brain distribution, oral erlotinib led, at the 650-mg dose, to significant increases in volume

Age dependency of cerebral P-glycoprotein function in wild-type and APPPS1 mice measured with PET. P-glycoprotein (P-gp, ABCB1) is an efflux transporter at the blood-brain barrier (BBB), which mediates clearance of beta-amyloid (Aβ) from brain into blood. We used ()-[C]verapamil PET in combination with partial P-gp inhibition with tariquidar to measure cerebral P-gp function in a beta -amyloidosis mouse model (APPtg) and in control mice at three different ages (50, 200 and 380 days). Following tariquidar pre-treatment (4 mg/kg), whole brain-to-plasma radioactivity concentration ratios () were significantly higher in APPtg than in wild-type mice aged 50 days, pointing to decreased cerebral P-gp function. Moreover, we found an age-dependent decrease in cerebral P-gp function in both wild

their cellular target organelles. Herein, we show that LysoTracker and MitoTracker Red are expelled from P-gp-overexpressing cancer cells, thus hindering their ability to fluorescently mark target organelles. We further demonstrate that tariquidar, a potent P-gp transport inhibitor, restores LysoTracker and MitoTracker Red cell entry. We conclude that LysoTracker and MitoTracker Red are P-gp transport

cells. In contrast, the noncompetitive high affinity P-gp inhibitor tariquidar fully restored JC-1 accumulation and the presence of the typical red fluorescence of J-aggregates. In the presence of tariquidar, measurement of the JC-1 fluorescence revealed similar levels of mitochondrial membrane potential in P-gp-negative (S) and P-gp-positive cells (R and T).