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Assessment of regional differences in tariquidar-induced P-glycoprotein modulation at the human blood-brain barrier.

ABSTRACT: We attempted to assess regional differences in cerebral P-glycoprotein (P-gp) function by performing paired positron emission tomography (PET) scans with the P-gp substrate (R)-[(11)C]verapamil in five healthy subjects before and after i.v. infusion of tariquidar (2 mg/kg). Comparison of tariquidar-induced changes in distribution volumes (DVs) in 42 brain regions of interest (ROIs) failed to detect significant differences among brain ROIs. Statistical parametric mapping analysis of parametric DV images visualized symmetrical bilateral clusters with moderately higher DV increases in response to tariquidar administration in cerebellum, parahippocampal gyrus, olfactory gyrus, and middle temporal lobe and cortex, which might reflect moderately decreased P-gp function and expression.

SUBMITTER: Bauer M

PROVIDER: S-EPMC2949150 | biostudies-literature | 2010 Mar

REPOSITORIES: biostudies-literature

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Assessment of regional differences in tariquidar-induced P-glycoprotein modulation at the human blood-brain barrier.

Bauer Martin M Karch Rudolf R Neumann Friederike F Wagner Claudia C CC Kletter Kurt K Müller Markus M Löscher Wolfgang W Zeitlinger Markus M Langer Oliver O

Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 20091216 3

We attempted to assess regional differences in cerebral P-glycoprotein (P-gp) function by performing paired positron emission tomography (PET) scans with the P-gp substrate (R)-[(11)C]verapamil in five healthy subjects before and after i.v. infusion of tariquidar (2 mg/kg). Comparison of tariquidar-induced changes in distribution volumes (DVs) in 42 brain regions of interest (ROIs) failed to detect significant differences among brain ROIs. Statistical parametric mapping analysis of parametric DV ...[more]

PMID: 20010957

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Project description: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 radiotracer injection), unlabeled tariquidar (3 mg/kg) was intravenously administered. Data were analyzed using 1-tissue 2-rate-constant (1T2K) and 2-tissue 4-rate-constant (2T4K) compartment models and either metabolite-corrected or uncorrected arterial input functions.After injection of (11)C-tariquidar or (11)C-elacridar, the brain PET signal corrected for radioactivity in the vasculature was low (~0.1 standardized uptake value), with slow washout. In response to tariquidar injection, a moderate but statistically significant rise in brain PET signal was observed for (11)C-tariquidar (+27% ± 15%, P = 0.014, paired t test) and (11)C-elacridar (+21% ± 15%, P = 0.014) without changes in plasma activity concentrations. Low levels of radiolabeled metabolites (<25%) were detected in plasma up to 60 min after injection of (11)C-tariquidar or (11)C-elacridar. The 2T4K model provided better data fits than the 1T2K model. Model outcome parameters were similar when metabolite-corrected or uncorrected input functions were used. There was no significant correlation between distribution volumes of (11)C-tariquidar or (11)C-elacridar and distribution volumes of (R)-(11)C-verapamil in different brain regions.The in vivo behavior of (11)C-tariquidar and (11)C-elacridar was consistent with that of dual Pgp/BCRP substrates. Both tracers were unable to visualize cerebral Pgp density, most likely because of insufficiently high binding affinities in relation to the low density of Pgp in human brain (?1.3 nM). Despite their inability to visualize Pgp density, (11)C-tariquidar and (11)C-elacridar may find use as a new class of radiotracers to study the interplay of Pgp and BCRP at the human BBB in limiting brain uptake of dual substrates.

Project description:UNLABELLED: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 effects associated with high doses of tariquidar. METHODS:Forty-two (11)C-dLop PET scans were obtained from 37 healthy volunteers. PET was performed with (11)C-dLop under the following 5 conditions: injected under baseline conditions without P-gp inhibition, injected 1 h after intravenous tariquidar infusion, injected during intravenous tariquidar infusion, injected after oral tariquidar, and injected after disulfiram. (11)C-dLop uptake was quantified with kinetic modeling using metabolite-corrected arterial input function or by measuring the area under the time-activity curve in the brain from 10 to 30 min. RESULTS:Neither oral tariquidar nor oral disulfiram increased brain uptake of (11)C-dLop. Injecting (11)C-dLop during tariquidar infusion, when plasma tariquidar concentrations reach their peak, resulted in a brain uptake of the radioligand approximately 5-fold greater than baseline. Brain uptake was similar with 2 and 4 mg of intravenous tariquidar per kilogram; however, the lower dose was better tolerated. Injecting (11)C-dLop after tariquidar infusion also increased brain uptake, though higher doses (up to 6 mg/kg) were required. Brain uptake of (11)C-dLop increased fairly linearly with increasing plasma tariquidar concentrations, but we are uncertain whether maximal uptake was achieved. CONCLUSION:We sought to increase the dynamic range of P-gp function measured after blockade. Performing (11)C-dLop PET during peak plasma concentrations of tariquidar, achieved with concurrent administration of intravenous tariquidar, resulted in greater P-gp inhibition at the human blood-brain barrier than delayed administration and allowed the use of a lower, more tolerable dose of tariquidar. On the basis of prior monkey studies, we suspect that plasma concentrations of tariquidar did not fully block P-gp; however, higher doses of tariquidar would likely be associated with unacceptable side effects.

Project description:Variation in the efficacy and safety of central nervous system drugs between humans and rodents can be explained by physiological differences between species. An important factor could be P-glycoprotein (Pgp) activity in the blood-brain barrier (BBB), as BBB expression of this drug efflux transporter is reportedly lower in humans compared to mouse and rat and subject to an age-dependent increase. This might complicate animal to human extrapolation of brain drug disposition and toxicity, especially in children. In this study, the potential species-specific effect of BBB Pgp activity on brain drug exposure was investigated. An age-dependent brain PBPK model was used to predict cerebrospinal fluid and brain mass concentrations of Pgp substrate drugs. For digoxin, verapamil and quinidine, in vitro kinetic data on their transport by Pgp were derived from literature and used to scale to in vivo parameters. In addition, age-specific digoxin transport was simulated for children with a postnatal age between 25 and 81 days. BBB Pgp activity in the model was optimized using measured CSF data for the Pgp substrates ivermectin, indinavir, vincristine, docetaxel, paclitaxel, olanzapine and citalopram, as no useful in vitro data were available. Inclusion of Pgp activity in the model resulted in optimized predictions of their brain concentration. Total brain-to-plasma AUC values (Kp,brain) in the simulations without Pgp were divided by the Kp,brain values with Pgp. Kp ratios ranged from 1 to 45 for the substrates investigated. Comparison of human with rodent Kp,brain ratios indicated ≥ twofold lower values in human for digoxin, verapamil, indinavir, paclitaxel and citalopram and ≥ twofold higher values for vincristine. In conclusion, BBB Pgp activity appears species-specific. An age-dependent PBPK model-based approach could be useful to extrapolate animal data to human adult and paediatric predictions by taking into account species-specific and developmental BBB Pgp expression.

Dataset Information

Assessment of regional differences in tariquidar-induced P-glycoprotein modulation at the human blood-brain barrier.

Publications

Assessment of regional differences in tariquidar-induced P-glycoprotein modulation at the human blood-brain barrier.

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