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SHORT COMMUNICATION

Influence of Hydroxyurea On Imatinib Mesylate (Gleevec) Transport at the Mouse Blood-Brain Barrier

Institut National de la Santé et de la Recherche Médicale, INSERM U 705, Université Paris 7, and Unité Mixte Recherche, Centre National de la Recherche Scientifique, CNRS 7157, Université Paris 5, Hôpital Fernand Widal, and Faculté de Pharmacie, Université Paris 5, Paris, France (S.B., J.-M.S.); and Department of Drug Metabolism and Pharmacokinetics, Novartis Pharma A.G., Basel, Switzerland (C.M., G.G., M.L.)

(Received May 5, 2006; accepted August 23, 2006)

	Abstract

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The combination of imatinib mesylate and hydroxyurea provides a therapeutic benefit in patients with glioblastoma, although each drug is not effective when used alone. The increase of brain delivery of one or both drugs has been suggested to be a potential cause of this therapeutic benefit. The cross-influence of hydroxyurea and imatinib on their respective brain distribution was examined in mice and rats. We used in situ brain perfusion in mice to determine whether these two drugs have an influence on their respective initial transport across the blood-brain barrier. The brain penetration of hydroxyurea, assessed by its brain uptake clearance, K_net, was low in mice (0.10 µl/g/s) and not modified by coperfusion of imatinib (0.5–500 µM). Likewise, the brain penetration of imatinib was low (K_net, 1.39 ± 0.17 µl/g/s) and not modified by direct coperfusion of hydroxyurea (0.2–1000 µM) or by intravenous pretreatment with 15 or 1000 mg/kg hydroxyurea. We also examined a potential time-dependent influence of hydroxyurea on imatinib brain distribution after sustained subcutaneous administration in rats using an implantable osmotic pump. The brain penetration of imatinib in rats increased with time, 1.6-fold (p < 0.01) after 7 and 14 days' infusion of imatinib (3 mg/day) with or without hydroxyurea (15 mg/day), and was not influenced by hydroxyurea. The results of these two sets of experiments indicate that hydroxyurea has no significant influence on the brain distribution of imatinib in mice and rats.

With the increasing understanding of the molecular basis of GBM oncogenesis, new therapeutic targets have been identified. There is a considerable body of evidence implicating the platelet-derived growth factor receptor autocrine stimulation in the pathogenesis of gliomas (Board and Jayson, 2005). Imatinib mesylate (Gleevec, formerly STI571, 4-[(4-methylpiperazin-1-yl)methyl]-N-[4-methyl-3-[(4-pyridin-3-ylpyrimidin-2-yl)amino]phenyl]benzamide methanesulfonate), an ATP competitive inhibitor, blocks the tyrosine kinase activity of various proteins, including ABL, BCR-ABL, c-KIT, and platelet-derived growth factor receptors. This drug is used in treatment of chronic myeloid leukemia and gastrointestinal stromal tumors (Dagher et al., 2002; Cohen et al., 2005). Preclinical studies have also suggested that imatinib could be effective for treating GBM (Kilic et al., 2000; Buchdunger et al., 2002).

Recently, two phase II studies evaluated the efficacy and safety of an innovative strategy for GBM treatment using a combination of imatinib and hydroxyurea, a ribonucleotide reductase inhibitor (Dresemann, 2005; Reardon et al., 2005). This combination seemed to be well tolerated and provided a durable antitumor activity in the patients included in these studies (n = 63 in total). Because both imatinib and hydroxyurea had poor efficacy when used alone in the treatment of GBM (Wen et al., 2002; Raymond et al., 2004), Dresemann and Reardon (2005) highlighted the unexpected therapeutic benefit of this combination and speculated about the mechanism(s) involved in this interaction. Of the various hypotheses, they suggested that cross-interactions on the passage of these drugs across the cerebral barriers could enhance the drug delivery into the brain, thereby enhancing their efficacy.

The brain penetration of imatinib is low in human and mouse (Dai et al., 2003; Le Coutre et al., 2004). In a previous study, we showed that the transport of imatinib across the mouse blood-brain barrier (BBB) is limited by active efflux transporters: P-glycoprotein (P-gp, Abcb1a/1b) and probably Breast cancer resistance protein 1 (Bcrp1, Abcg2) (S. Bihorel, G. Camenisch, N. Lemaire, and J.-M. Scherrmann, submitted for publication). Likewise, hydroxyurea poorly enters the brain of guinea pigs and seems to be substrate of a digoxin-sensitive efflux transport (Dogruel et al., 2003). Thus, P-gp was suggested to restrict the passage of hydroxyurea into the brain of guinea pigs.

In this study, the potential pharmacokinetic interaction between hydroxyurea and imatinib on their respective brain delivery, with special attention turned to the influence of hydroxyurea on the brain penetration of imatinib, was investigated in mouse and rat. In situ brain perfusion was used in mice to assess brain penetration of hydroxyurea and imatinib in the presence of the corresponding competitor. This very sensitive method is designed to specifically assess the kinetics and the mechanisms of transport of solutes at the luminal side of the BBB. It avoids any peripheral distribution or metabolic interference, because the blood circulation to the brain is taken over by a perfusion fluid containing the solute of interest and administered by catheterization of the carotid artery. This method also respects the physiological properties of the BBB. Finally, we investigated a potential time-dependent effect of hydroxyurea on the brain penetration of imatinib in rats after a 2-week continuous subcutaneous administration of imatinib alone or in combination with hydroxyurea.

	Materials and Methods

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Chemicals and Reagents. [¹⁴C]Imatinib (1.94 GBq/mmol) and unlabeled imatinib (both as mesylate salts) were kindly provided by Novartis Pharma (Basel, Switzerland). [¹⁴C]Hydroxyurea (1.98 GBq/mmol) was purchased from American Radiolabeled Chemicals Inc. (Saint Louis, MO). [³H]Sucrose (0.43 TBq/mmol) and unlabeled hydroxyurea were purchased from Sigma-Aldrich (Buchs, Switzerland). All other chemicals were of analytical grade. The doses or concentrations mentioned in the following text refer to the base form of compounds.

Animals. All experiments were performed on adult male FVB mice (weighing 20–30 g) and Hanover Wistar rats (weighing 270–310 g) supplied by Charles River (L'Arbresles, France). The animals were kept under standard conditions of temperature and lighting with free access to food and water. These studies complied with the Swiss Federal Act on Animal Protection (revised 2003) and with the Swiss Animal Protection Ordinance (revised 2001).

In Situ Brain Perfusion Procedure in Mice. The transport of imatinib and hydroxyurea into the brain compartment was assessed by in situ brain perfusion. The details of this model have been described previously (Dagenais et al., 2000; Smith and Allen, 2003). In brief, mice were anesthetized with a mixture of xylazine (8 mg/kg; Bayer, Leverkusen, Germany) and ketamine (140 mg/kg; Graeub, Bern, Switzerland) given i.p. The right common carotid artery was exposed and ligated on the heart side. The external carotid artery was ligated rostral to the occipital artery at the bifurcation of the common carotid artery with the internal carotid. Then, the right common carotid artery was catheterized with polyethylene tubing (0.28 mm i.d. x 0.61 mm o.d.; Smiths Medical, Hythe, UK) containing 25 units/ml heparin. The thorax of the mouse was opened and the heart cut immediately before starting perfusion (flow rate, 2.5 ml/min). The perfusion fluid consisted of bicarbonate-buffered physiological saline: 128 mM NaCl, 24 mM NaHCO₃, 4.2 mM KCl, 2.4 mM NaH₂PO₄, 1.5 mM CaCl₂, 0.9 mM MgSO₄, and 9 mM D-glucose. The solution was gassed with 95% O₂-5% CO₂ for oxygenation and pH control (7.4) and warmed to 37°C. All mice were perfused with the test compounds, [¹⁴C]imatinib (0.6–1.4 kBq/ml) or [¹⁴C]hydroxyurea (0.9–1.8 kBq/ml), plus [³H]sucrose (6.5–30 kBq/ml) as a vascular marker. [¹⁴C]Hydroxyurea was dissolved in 0.9% NaCl, whereas [¹⁴C]imatinib and [³H]sucrose were dissolved, respectively, in a 1:1 and 1:9 mixture of ethanol/water v/v. The perfusions were terminated by decapitation after 60 and 120 s for [¹⁴C]imatinib and [¹⁴C]hydroxyurea uptake experiments, respectively. The brain was quickly extracted from the skull and dissected on ice. The right cerebral hemisphere was sampled and weighed in a tared vial. Finally, aliquots of the perfusion solution were collected from the catheter and weighed to determine the concentration of tracers in the perfusate. All samples were digested with 1 ml of Biolute-S (Zinsser Analytic, Frankfurt, Germany) overnight at room temperature and mixed with 500 µl of 2 NHCl and 10 ml of IrgaSafe-Plus (Zinsser). ³H and ¹⁴C labels were counted simultaneously in a Tricarb 2500TR Liquid Scintillation Analyzer (PerkinElmer Life and Analytical Sciences, Boston, MA).

The brain uptake of hydroxyurea was examined over a large concentration range (0.5–500 µM). We also studied the influence of imatinib coperfusion (0.5–500 µM) on the brain penetration of hydroxyurea (1 µM), as well as the influence of hydroxyurea coperfusion (0–1000 µM) on the brain penetration of imatinib (0.5 µM). Finally, the brain penetration of 0.5 µM imatinib was measured in mice that had received, 15 min or 1 h before starting perfusion, an intravenous administration (5 ml/kg) of 0.9% NaCl, hydroxyurea (15 or 1000 mg/kg) (both dosages prepared in 0.9% NaCl) in the exposed saphenous vein.

All calculations of BBB transport parameters were performed as described previously (Takasato et al., 1984; Smith, 1996). The brain vascular volume (V_vasc, µl/g) was estimated from the brain distribution volume of [³H]sucrose using the following equation: V_vasc = X*/C*_perf, where X* (dpm/g) is the concentration of [³H]sucrose in the right cerebral hemisphere and C*_perf (dpm/µl) is the concentration of [³H]sucrose in the perfusion solution.

The transport of imatinib or hydroxyurea toward brain is expressed as the net transport coefficient (K_net, µl/g/s), which corresponds to the brain uptake clearance. It was calculated using the following equation, which includes a correction for vascular contamination: K_net = (X_tot – V_vasc x C_perf)/(C_perf x T), where X_tot (dpm/g) is the concentration of radiolabeled test drug found in the brain tissue sample, i.e., microvasculature plus extravascular material, C_perf (dpm/µl) the concentration of radiolabeled test drug in the perfusate, and T the perfusion time (seconds).

Impact of Hydroxyurea on the Brain Penetration of Imatinib at Steady State in Rats. Hanover Wistar rats received subcutaneously imatinib, 3 mg/day (1.4 MBq/day), either alone or in combination with hydroxyurea, 15 mg/day, both released by 2ML2 Alzet osmotic pumps (delivery flow, 4.5 µl/h; Charles River). The pumps were inserted subcutaneously in the back of each rat anesthetized by inhalation of isoflurane (Abbott AG, Baar, Switzerland). The solution containing the test compounds was prepared in 0.9% NaCl to achieve appropriate concentrations and sterilized by filtration on a 0.2-µm polyethersulfone-based membrane (Waters AG, Rupperswil, Switzerland) just before filling the pumps. The animals were sacrificed 24, 192 (day 7), or 336 h (day 14) after implantation of the pump (n = 3 per time point). Blood (10 ml) was collected by puncture into the vena cava. Brain was sampled and quickly cleaned to remove the largest blood vessels. Blood and brain samples were immediately stored at –20°C pending analysis. Brain samples were homogenized just before analysis in 10 ml of demineralized water.

The concentrations of unchanged imatinib in blood (200 µl) and brain (500 µl of homogenate) were determined by liquid chromatography as described previously (S. Bihorel, G. Camenisch, N. Lemaire, and J.-M. Scherrmann, submitted for publication). The brain penetration of imatinib was estimated by the brain-to-blood concentration ratios at steady state (K_p).

Statistical Analysis. All values are presented as means ± S.D. for three to five mice in the in situ brain perfusion experiment or three rats in the steady-state pharmacokinetic study. K_net values, obtained by in situ brain perfusion, were compared by one-way analyses of variance followed by multiple comparisons to the control group using Dunnett's tests (SigmaStat 3.11; SPSS Inc., Chicago, IL). Imatinib K_net values obtained in mouse pretreated with hydroxyurea were compared using a two-way analysis of variance, to investigate the influence of the pretreatment dose and time. Imatinib blood concentrations and K_p values observed at different times after continuous administration of imatinib were compared by two-way analyses of variance on log-transformed values, followed by multiple comparisons using Tukey's tests (SigmaStat 3.11). In all analyses, the statistical significance was set at p < 0.05.

	Results and Discussion

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Various concentrations of hydroxyurea and imatinib were perfused into the brains of mice with or without the corresponding competitor, and always in the presence of the vascular space marker [³H]sucrose. The brain distribution volume of [³H]sucrose was similar in all experiments (overall mean of 17.4 ± 1.8 µl/g; data not shown) and consistent with the values (13–17 µl/g) usually reported for sucrose (Dagenais et al., 2000; Cisternino et al., 2004). This result suggests that the mouse BBB remained intact during all perfusion experiments with hydroxyurea and imatinib.

The K_net of hydroxyurea (mol. wt. = 76.06, log P =–1.27) after 120 s of perfusion was low (0.10 µl/g/s) and concentration-independent (0.5–500 µM; Fig. 1A). Using the same technique, previous studies have shown that the K_net of drugs can range from 0.03 µl/g/s for morphine-6-glucuronide (mol. wt. = 462.14, log P =–2.4), a compound with very low brain penetration, to more than 40 µl/g/s for drugs that can freely cross cell membranes, like diazepam (mol. wt. = 284.74, log P = 2.8) (Dagenais et al., 2000; Bourasset and Scherrmann, 2006). Hydroxyurea K_net was not significantly increased by simultaneous perfusion of 0.5 to 500 µM imatinib (Fig. 1B). These data indicate that the initial transport of hydroxyurea across the mouse BBB is low, independent of any saturable mechanism, and not enhanced by imatinib. Recently, Dogruel et al. (2003) showed that [¹⁴C]hydroxyurea crosses the brain barriers of guinea pigs at a slow rate and that its distribution in cerebrum can be significantly increased by coperfusion of 200 µM hydroxyurea or 25 µM digoxin after 20 min of perfusion (Dogruel et al., 2003). This finding suggests that a digoxin-sensitive efflux mechanism transports hydroxyurea out of guinea pig brain, after long exposure. Therefore, we cannot exclude the possibility that a similar mechanism, perhaps influenced by imatinib, removes hydroxyurea from the brain of mice when the drug distribution equilibrium is reached into the whole brain. Unfortunately, our study was not expanded to investigate this issue, inasmuch as the in situ brain perfusion procedure in mouse is not designed to perform long perfusion (Dagenais et al., 2000).

View larger version (25K): [in this window] [in a new window]   FIG. 1. A, brain transport coefficient (Knet, µl/g/s) of [14C]hydroxyurea in mice measured after in situ brain perfusion for 120 s. Points, means; bars, S.D. for four to five animals. B, [14C]hydroxyurea Knet measured after in situ brain perfusion (120 s) of the drug (1 µM) with various concentrations of imatinib in mice. Columns, means; bars, S.D. for four to five animals. , p < 0.05, control mice perfused with 0.5 µM hydroxyurea versus mice coperfused with 0.5 µM hydroxyurea and imatinib. C, [14C]imatinib mesylate Knet measured after in situ brain perfusion (60 s) of the drug (0.5 µM) with various concentrations of hydroxyurea in mice. Columns, means; bars, S.D. for three to five animals. D, [14C]imatinib mesylate Knet, measured after in situ brain perfusion (60 s) in mice; the mice received 0.9% NaCl, 15 mg/kg or 1000 mg/kg hydroxyurea 15 min (open columns) or 1 h (closed columns) before starting perfusion. Columns, means; bars, S.D. for four to five animals.

In a previous work, we examined the brain penetration of imatinib in wild-type and P-gp or Bcrp1 knockout mice and found that it was limited by efflux transporters, P-gp and probably Bcrp1 (S. Bihorel, G. Camenisch, N. Lemaire, and J.-M. Scherrmann, submitted for publication). In the present study, the brain of wild-type mice was perfused with 0.5 µM imatinib and increasing concentration of hydroxyurea (0.2–1000 µM), to study the potential effect of hydroxyurea on P-gp and Bcrp1-mediated efflux. The imatinib K_net value in the absence of hydroxyurea (1.39 ± 1.7 µl/g/s) was in line with our previous experiments. Moreover, coperfusion of hydroxyurea did not significantly modify the brain penetration of imatinib (Fig. 1C).

The drug-binding sites on P-gp are known to lie within the transmembrane domains of the protein (Ambudkar et al., 2003); less is known about the molecular interactions between Bcrp1 and its substrates. Considering the low brain penetration of hydroxyurea after 120 s of perfusion, the amounts of drug that had access to the drug-binding sites on P-gp and Bcrp1 after 1 min of perfusion might have been very low and insufficient to influence the efflux of imatinib. Therefore, we measured imatinib K_net in mice pretreated with hydroxyurea: physiological 0.9% NaCl, or low (15 mg/kg) or high doses (1000 mg/kg) of hydroxyurea were administered intravenously in FVB mice 15 min or 1 h before starting perfusion. The brain penetration of imatinib was not significantly increased under these conditions. Together, these results suggest that hydroxyurea does not influence the transport of imatinib at the mouse BBB (Fig. 1D).

The patients, whose GMB positively responded during the two abovementioned phase II studies, received oral dosages of imatinib and hydroxyurea on a continuous daily schedule (Dresemann, 2005; Reardon et al., 2005). Therefore, it is possible that one drug had a time-dependent influence on the systemic or brain pharmacokinetics of the other. In one of these studies, the pharmacokinetics of imatinib and hydroxyurea were examined after 1 day or 28 days of treatment in patients comedicated, or not, with enzyme-inducing antiepileptic drugs (EIAEDs) (Reardon et al., 2005). At day 1 or at steady state, the kinetic parameters of imatinib in patients not treated with EIAEDs were similar to those obtained in patients only treated with a similar daily dosage of imatinib (Le Coutre et al., 2004; Peng et al., 2004). Likewise, there was no significant difference between imatinib plasma protein binding obtained in the presence or absence of hydroxyurea (Kretz et al., 2004; Reardon et al., 2005). This suggests that hydroxyurea does not significantly modify the systemic pharmacokinetics of imatinib. In contrast, the pharmacokinetics of hydroxyurea at steady state seem to be slightly altered in patients comedicated with imatinib (with or without EIAED comedication) (Tracewell et al., 1995; Villani et al., 1996; Reardon et al., 2005). The variations include a modest 2-fold increase in the apparent clearance of hydroxyurea, a 2-fold decrease in plasma exposure, and lower peak concentrations in plasma. Therefore, they should not result in any improvement in the brain penetration of hydroxyurea. Furthermore, the extent of hydroxyurea binding to plasma proteins has not been published. Finally, these data indicate that the combination of hydroxyurea and imatinib is unlikely to enhance the brain delivery of one or both drugs by an increase in their systemic concentration.

View larger version (16K): [in this window] [in a new window]   FIG. 2. Blood concentrations (A) and brain-to-blood concentration ratios (brain Kp; B) of imatinib in rats at various time points; the animals subcutaneously received either 3 mg/day [14C]imatinib mesylate (open columns) or 3 mg/day [14C]imatinib mesylate plus 15 mg/day hydroxyurea (closed columns) released by 2ML2 Alzet osmotic pumps.

In summary, the results reported here in healthy rodents suggest that hydroxyurea does not modify the brain penetration of imatinib after short or sustained coadministration. Likewise, we found that imatinib had no influence on the initial transport of hydroxyurea in the mouse BBB. Whether imatinib inhibits the activity of an efflux transport of hydroxyurea at brain distribution equilibrium remains unknown. Additional studies should further characterize this interaction on preclinical tumor models, because the permeability properties of the cerebral endothelium are probably modified in capillaries that irrigate the GBM tumor. Lastly, the uptake of imatinib and hydroxyurea into tumor cells should be examined, as well as their potential cross-influence.

	Acknowledgments

 
We thank Dr. Rachael Profit for proofreading the manuscript.

	Footnotes

 
This project was supported by Novartis Pharma AG contract (Novartis-INSERM n° 03035A10).

Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

doi:10.1124/dmd.106.010975.

ABBREVIATIONS: GBM, glioblastoma; BBB, blood-brain barrier; Bcrp1, breast cancer resistance protein 1; EIAED, enzyme-inducing antiepileptic drug; K_net, brain uptake clearance; K_p, brain-to-blood concentration ratio at steady state; P-gp, P-glycoprotein.

Address correspondence to: Prof. Jean-Michel Scherrmann, INSERM U705, Hôpital Fernand Widal, 300, rue du Fbg Saint-Denis, 75475 Paris Cedex 10, France. E-mail: jean-michel.scherrmann{at}fwidal.inserm.fr

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