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Drug Metabolism and Disposition Fast Forward
First published on March 10, 2006; DOI: 10.1124/dmd.105.006429

0090-9556/06/3406-971-975$20.00
DMD 34:971-975, 2006

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IN VITRO BLOOD DISTRIBUTION AND PLASMA PROTEIN BINDING OF THE IRON CHELATOR DEFERASIROX (ICL670) AND ITS IRON COMPLEX FE-[ICL670]2 FOR RAT, MARMOSET, RABBIT, MOUSE, DOG, AND HUMAN

H. Markus Weiss, Marcel Fresneau, Gian P. Camenisch, Olivier Kretz, and Gerhard Gross

Novartis Pharma AG, Exploratory Development/Drug Metabolism and Pharmacokinetics, Basel, Switzerland

(Received July 5, 2005; Accepted March 9, 2006)


   Abstract
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 Abstract
Materials and Methods
 Results
 Discussion
 References
 
Deferasirox (Exjade, ICL670) is an orally active iron chelator. Two molecules of deferasirox can form a complex with ferric iron (Fe-[ICL670]2) that can be excreted, reducing body iron overload. The blood binding parameters across species and the interaction with human serum albumin were analyzed for deferasirox and its iron complex. Both molecules were very highly bound to plasma proteins in all the tested species with unbound fractions in plasma in the range of 0.4 to 1.8% and 0.2 to 1.2% for deferasirox and Fe-[ICL670]2, respectively; binding of the iron complex was either similar or higher in all the species. The high plasma protein binding was in line with a distribution mainly into the plasma fraction of blood; the fraction in plasma was around 100% for Fe-[ICL670]2 in all the species and 65 to 95% for deferasirox depending on the species. Investigations with isolated proteins pointed to serum albumin as the principal binding protein for deferasirox and its iron complex in human plasma. Competition binding experiments indicated that deferasirox at high concentrations displaced markers from the two main drug binding sites of human albumin, whereas Fe-[ICL670]2 displaced only warfarin. In the context of the pharmacokinetic properties of deferasirox and Fe-[ICL670]2, the data indicate the importance of plasma protein binding for their disposition and support a comparison of the pharmacokinetics of deferasirox and its iron complex across species. The low likelihood of clinically relevant drug displacement by deferasirox in plasma is discussed.

Iron accumulation to toxic and eventually lethal levels can result from repeated blood transfusions (e.g., in ß-thalassemia major and sickle cell disease) or from excessive dietary iron uptake because humans are unable to actively eliminate iron from the body. Iron chelators slowly mobilize deposits of accumulated iron, most likely by continuously binding the small amounts of soluble iron in the "labile pool," which are in equilibrium with the insoluble hemosiderins (Crichton and Ward, 2003Go). Deferasirox (Exjade, ICL670, Novartis Pharma AG, Basel, Switzerland) is an orally active iron chelator under development (Nick et al., 2003Go; Nisbet-Brown et al., 2003Go) and recently approved by some health authorities, including the U.S. Food and Drug Administration. Two molecules of deferasirox can form a complex with ferric iron (Fe-[ICL670]2) (Fig. 1) (Steinhauser et al., 2004Go); solubilized, chelated iron is then excreted.


Figure 1
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  		FIG. 1. Structure of 14C-labeled deferasirox (A) and its iron complex (B). Deferasirox was labeled with one 14C atom per molecule; however, in each molecule, the two given different positions of the label (*) are theoretically possible. Deferasirox binds iron (Fe3+) in a meridional orientation. At physiological pH, deferasirox and its iron complex carry one and three negative charges, respectively.

 
For many years, Desferal (deferoxamine mesylate) has been the only iron chelator approved for general use. However, its unfavorable pharmacokinetics (very short plasma half-life and poor oral bioavailability) (Porter, 2001Go) necessitate special modes of application (daily s.c. or i.v. infusions) that are poorly accepted by many patients. This leads to poor compliance, despite the bad prognosis of untreated iron overload. An orally active iron chelator would be expected to improve the compliance and, therefore, the clinical responses, will be usable in areas with less developed infrastructure, and can facilitate the treatment of other diseases, including nontransfusion-dependent thalassemias, anemias, and possibly hemochromatosis. The blood binding parameters of a drug can be critical for its pharmacokinetics and are needed for a comparison of pharmacokinetics across species. Here we report the blood distribution and plasma protein binding of deferasirox and its iron complex for species used in preclinical safety investigations and healthy humans, as well as characterize the interaction of the two molecules with human serum albumin (HSA). The employed concentrations cover the clinically and preclinically relevant range.


   Materials and Methods
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 Abstract
 Materials and Methods
Results
 Discussion
 References
 
Materials. Deferasirox (C21H15N3O4, molecular weight 373.4), Fe-[ICL670]2 (tri-sodium salt, >95% pure), [14C]deferasirox (0.29-2.0 MBq/mg, 98% pure), and [14C]Fe-[ICL670]2 (0.25-1.7 MBq/mg, tri-sodium salt, 98% pure) were synthesized at Novartis Pharma AG (Fig. 1). [14C]Diazepam (7.2 MBq/mg, 99% pure) and [14C]warfarin (6.68 MBq/mg, 99% pure) were obtained from Amersham Pharmacia Biotech (Little Chalfont, UK). Used stock solutions were in ethanol (deferasirox, warfarin, and diazepam) or water (Fe-[ICL670]2). Centrifree and Microcon devices (molecular cutoff of 30 kDa) were obtained from Amicon (Beverly, MA), and phosphate-buffered saline (PBS) was obtained from Gibco (D-PBS; Paisley, Scotland). HSA (A-1887), {alpha}1-acid glycoprotein (G-9885), and {gamma}-globulins (G-4386) were purchased from Sigma (St. Louis, MO). Human high density lipoprotein (437641), low density lipoprotein (437644), and very low density lipoprotein (437647) were purchased from Calbiochem (San Diego, CA). Solutions of HSA, {alpha}1-acid glycoprotein, and {gamma}-globulins were prepared in PBS. The lipoproteins were delivered as solutions in 150 mM NaCl and 0.01% EDTA, pH 7.4. The concentrations of the lipoproteins as given by the manufacturer were adjusted to the used concentrations with PBS. Human blood was taken from healthy male volunteers. Rat blood was from male albino rats (Hanover, Wistar); mouse blood was from male p53 wild-type mice (B6.129-Trp53tm1Brd+ N5); dog blood was from male beagles; monkey blood was from male and female marmoset monkeys (Callithrix jacchus); and rabbit blood was from male and female rabbits (New Zealand White). Heparin was used as anticoagulant, and all the blood and plasma specimens were pooled (n ≥ 3, with the exception of marmoset blood, which was from one male and one female animal). Fresh blood was used within 24 h (marmoset blood was slightly older because of the necessity of shipment); plasma was defrosted from storage at -20°C.

Control Experiments. Control experiments in PBS at 20 and 80 µg/ml deferasirox or Fe-[ICL670]2 indicated that ultrafiltration was a suitable method to determine the protein binding: the permeation through the filtration membrane was ≥0.8 for deferasirox and ≥0.95 for Fe-[ICL670]2, indicating no major retention. Only total radioactivity was measured in all the experiments; therefore, some bias resulting from labeled impurities or degradation products cannot be completely excluded. Thirty disintegrations per minute above background (14C) was defined as the limit of quantification for radioactivity analysis; all the reported values were above this limit.

In vitro interconversion between deferasirox and its iron complex was investigated in rat blood and plasma at 37°C (Novartis, unpublished data). Iron complex formation in plasma spiked with 4 or 80 µg/ml deferasirox was ≤5 or ~2%, respectively, after 1 h of incubation. Iron complex decay in plasma spiked with 4 or 80 µg/ml Fe-[ICL670]2 was about 22 or 7%, respectively, after 1 h of incubation. Because both forms of deferasirox are very highly bound to plasma proteins, the data on binding in plasma reported here do not contain a strong bias as a result of complex formation or decay. Iron complex formation in blood spiked with 4 or 80 µg/ml deferasirox was ≤5 or ~2%, respectively, after 1 h of incubation. Iron complex decay in blood spiked with 4 or 80 µg/ml Fe-[ICL670]2 was about 17 or 5%, respectively, after 1 h of incubation. Because the blood distribution of both forms of deferasirox was similar (see Table 1), most of the data on blood distribution reported here do not contain a relevant bias as a result of complex formation or decay. Only incubations with low concentrations of [14C]Fe-[ICL670]2 might slightly underestimate the fraction in plasma of total amount in blood (fp) because of some decay of the iron complex.


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  		TABLE 1 In vitro blood distribution and plasma protein binding of [14C]deferasirox and its iron complex [14C]Fe-[ICL670]2 for rat, marmoset, rabbit, mouse, dog, and human Given numbers are mean ± S.D. of triplicate determinations.

 

Blood Distribution. Fresh blood was spiked to the desired compound concentrations. First, kinetics of distribution were determined. In all the experiments reported here, incubations were for 1 h at 37°C, which was sufficient to reach equilibrium. Sedimentation of cells was by centrifugation (1500g, 10 min, 37°C). Radioactivity was measured in blood (Cb) before and in plasma (Cp) after centrifugation, and hematocrit (H) was determined in triplicate. The fraction in plasma (fp) was calculated as follows: fp(%) = (Cp/Cb) x (1-H) x 100.

Plasma Protein Binding. Plasma or solutions of plasma proteins in PBS were spiked to the desired compound concentrations. All the incubations were for 1 h at 37°C before centrifugation in Centrifree or Microcon (mouse and marmoset plasma and lipoprotein solutions) devices (7-10 min, 2000g, 37°C, ~20% of sample filtered, shorter centrifugation times for protein solutions). Radioactivity was determined in the spiked solution (Ct) and the ultrafiltrate (Cu). The unbound fraction (fu) was calculated as follows: fu(%) = Cu/Ct x 100.

IC50 values were determined from competition data by nonlinear least-squares fitting to the four-parameter logistic function using Sigma Plot (Systat Software Inc., Richmond, CA).


   Results
Top
 Abstract
 Materials and Methods
 Results
Discussion
 References
 
In the investigated concentration range (4-80 µg/ml, 11-214 µM for deferasirox and 5.4-107 µM for Fe-[ICL670]2; see Table 1 for details), [14C]deferasirox and [14C]Fe-[ICL670]2 were mainly located in the plasma fraction of blood. In all the investigated species, fp was clearly higher for the iron complex [14C]Fe-[ICL670]2, which was almost quantitatively located in plasma (fp, ~100%). Blood distribution of [14C]deferasirox was species-dependent (Table 1), with humans showing the highest plasma fraction (95%) and rats the lowest (~67%). In some species (male and female mouse, male and female rabbit), a trend for a decrease in fp with increasing compound concentration was visible, whereas in others this was not apparent.

Both deferasirox and its iron complex Fe-[ICL670]2 were very highly bound to plasma proteins with unbound fractions in the range of 0.4 to 1.8% and 0.2 to 1.2% for deferasirox and Fe-[ICL670]2, respectively (Table 1). The unbound fraction of Fe-[ICL670]2 was similar or slightly smaller as compared with deferasirox for mouse, rabbit, marmoset, and human, as well as clearly smaller for rat and dog. Species differences in plasma protein binding were apparent for deferasirox and Fe-[ICL670]2; from the tested species, humans showed the highest bound fraction for deferasirox (99.5%) in line with the highest fraction in plasma. For deferasirox and Fe-[ICL670]2, a slight trend for increasing fu with higher compound concentrations was evident in some species but clearly not in the marmoset.

Binding to isolated human plasma proteins was measured at physiologically relevant concentrations of the major plasma proteins involved in drug binding (Table 2). Unbound fractions determined in the presence of the tested plasma proteins indicated that both deferasirox and its iron complex were predominantly bound to HSA. Both deferasirox and Fe-[ICL670]2 were not significantly bound to hemopexin, a heme-binding plasma glycoprotein (data not shown).


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  		TABLE 2 In vitro binding of [14C]deferasirox and its iron complex [14C]Fe-[ICL670]2 to isolated human plasma proteins Given numbers are mean ± S.D. of triplicate determinations. Used plasma protein concentrations are in the range of concentrations found in plasma of healthy subjects with the exception of 1 mg/ml HSA.

 

In human plasma, displacement of both diazepam and warfarin at high concentrations of deferasirox was found (Table 3). At a concentration of 100 µg/ml (268 µM) deferasirox, the unbound fractions of diazepam and warfarin in human plasma were 3.5 and 1.5%, respectively, as compared with 2.3 and 1.2% in the absence of deferasirox. In contrast, no increase of the unbound fraction of diazepam and warfarin occurred in human plasma at concentrations of up to 100 µg/ml (134 µM) Fe-[ICL670]2. In addition to the displacement experiments in plasma, displacement of diazepam and warfarin in a solution of HSA (1 mg/ml, 15 µM, ~2.5% of the plasma albumin concentration) was analyzed. Deferasirox displaced diazepam (0.1 µg/ml, 0.35 µM) from HSA with an IC50 of 46 µg/ml (123 µM), whereas Fe-[ICL670]2 did not at concentrations of up to 100 µg/ml (134 µM). Warfarin (1 µg/ml, 3.2 µM) was displaced from HSA by deferasirox and Fe-[ICL670]2 with IC50 values of 84 µg/ml (225 µM) and 41 µg/ml (55 µM), respectively (Table 3).


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  		TABLE 3 Displacement of [14C]warfarin or [14C]diazepam from human plasma proteins by deferasirox and its iron complex Given numbers are mean ± S.D. of triplicate determinations for the unbound fractions of [14C]warfarin or [14C]diazepam in human plasma (%) in the absence and presence of deferasirox and Fe-[ICL670]2. For the IC50 values, 95% confidence intervals of the fit are given in brackets; all the R2 values were >0.99.

 


   Discussion
Top
 Abstract
 Materials and Methods
 Results
 Discussion
References
 
Deferasirox and its iron complex were very highly bound to plasma proteins in all the investigated species. The very high binding to plasma protein is in line with the predominant distribution of deferasirox and Fe-[ICL670]2 into the plasma fraction of blood. The very high protein binding in combination with a small to moderate (deferasirox, determined for rat and human) or small (Fe-[ICL670]2, determined for rat) volume of distribution (Galanello et al., 2003Go) (Novartis, unpublished data; H. Wiegand, A. Schweitzer, F. Waldmeier, G. Bruin, T. Falle, and G. Gross, manuscript in preparation) emphasizes the relevance of the plasma protein binding for the distribution, the systemic exposure, and the pharmacokinetics of deferasirox and its iron complex. For iron chelators, a reasonably high systemic exposure and lasting presence in plasma should allow for efficient protection against the harmful effects of circulating nontransferrin-bound plasma iron (Hershko et al., 1998Go). The reported protein binding and blood distribution data are significant for a comparison of pharmacokinetics of deferasirox and its iron complex across species and for interspecies scaling and to allow for a meaningful referencing of pharmacokinetic parameters to either blood or plasma concentrations (Hinderling, 1997Go).

The overall binding of deferasirox and its iron complex in human plasma is mainly caused by binding to albumin. For Fe-[ICL670]2, the unbound fraction in the presence of 40 mg/ml HSA, a concentration typically found in human plasma, was virtually identical to the unbound fraction found in plasma, whereas binding to all the other tested plasma proteins was negligible in comparison (Table 2). This suggests that protein binding of Fe-[ICL670]2 in human plasma is almost exclusively the result of binding to HSA. For deferasirox, the unbound fraction in the presence of 40 mg/ml HSA was somewhat higher as compared with the unbound fraction in human plasma. Therefore, binding to, for example, lipoproteins may contribute to some extent to the overall binding in plasma, but HSA is again clearly the main binder. No strong increase of the unbound fraction at high concentrations (80 µg/ml) of deferasirox or its iron complex indicated a very high binding capacity for both molecules in plasma of all the tested species. This is in agreement with albumin being the main binding protein because albumin is, in the absence of a severe clinical condition like liver impairment, present at high concentrations.

Deferasirox at high concentrations displaced marker compounds for the two main binding sites for anionic drugs on HSA (Sudlow et al., 1976Go) in whole human plasma and on the isolated HSA. The observed displacement could be because of a direct competition at the binding site and/or an allosteric interaction. Despite the very high plasma protein binding of the iron complex, neither warfarin (marker for Sudlow's site I) nor diazepam (marker for Sudlow's site II) was displaced by the complex in plasma; the unbound fraction of diazepam was even slightly reduced. In experiments with isolated HSA, the unbound fraction of diazepam also decreased in presence of Fe-[ICL670]2 (data not shown). The increased binding of diazepam in the presence of Fe-[ICL670]2 points to an allosteric interaction of the complex with HSA, a frequently observed phenomenon (Chen and Hage, 2004Go). From isolated HSA, warfarin was displaced by Fe-[ICL670]2, whereas in plasma no displacement was evident (Table 3), probably because of the higher albumin concentration in the latter experiment. The observed displacement from HSA could be because of a direct competition at the binding site or an allosteric interaction. Recent data from cocrystallization experiments indicate that phenyl-butazone and indomethacin can bind simultaneously to Sudlow's site I (Ghuman et al., 2005Go). These structural data show that the size and the flexibility of this binding site should not only allow for binding of deferasirox but also of its relatively bulky iron complex. In addition, Ghuman et al. (2005Go) show that many drugs bind to albumin also at a secondary or even tertiary binding site. In the case of deferasirox and its iron complex, binding to several sites could explain the relatively high concentrations of the compounds necessary to displace warfarin, despite their very high binding to albumin.

Patients treated with deferasirox in clinical trials experienced high plasma concentrations of up to 250 µM deferasirox at supratherapeutic doses; concentrations of the iron complex were severalfold lower (Galanello et al., 2003Go; Nisbet-Brown et al., 2003Go). Even though the binding capacity of albumin in plasma is very high because of its high concentration of about 40 mg/ml (0.6 mM) in healthy human subjects, some displacement of other HSA-bound drugs can occur at such high drug concentrations. Displacement of drugs from binding sites on plasma proteins has been discussed as a mechanism of clinically relevant drug-drug interaction. However, there is broad agreement that even though displacement can occur, the effect is usually limited to a change in the total plasma concentration of the displaced drug with an unchanged or only temporarily changed exposure to unbound drug and no need for dose adjustment (Rolan, 1994Go; Sansom and Evans, 1995Go; Benet and Hoener, 2002Go). A clinical significance of displacement by deferasirox cannot be completely excluded but is restricted to the very rare cases of highly protein-bound drugs with a narrow therapeutic index that are either given parenterally and have a high extraction ratio or that are given orally and have a very rapid pharmacokinetic-pharmacodynamic equilibration time (Sansom and Evans, 1995Go; Benet and Hoener, 2002Go).


   Acknowledgments
 
We thank Heidi Hügli for skillful technical assistance, Matthias Frommherz and Dietmar Schmid for preparation of the radiolabeled deferasirox and its iron complex, and Marina Tintelnot-Blomley, Hans-Peter Gschwind, Handan He, Romain Sechaud, Hanspeter Nick, Ernst Ulrich Kölle, and Martin Schumacher for helpful discussions and comments on the manuscript.


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

doi:10.1124/dmd.105.006429.

ABBREVIATIONS: deferasirox, 4-[3,5-bis-(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]-benzoic acid; ICL670, compound code for deferasirox; HSA, human serum albumin; PBS, phosphate-buffered saline; fp, fraction in plasma of total amount in blood; fu, unbound fraction in plasma.

Address correspondence to: Markus Weiss, Novartis Pharma AG, ED/DMPK/ADME, WKL-135.4.83, CH-4002 Basel, Switzerland. E-mail: markus.weiss{at}novartis.com


   References
Top
 Abstract
 Materials and Methods
 Results
 Discussion
 References
 


Benet LZ and Hoener BA (2002) Changes in plasma protein binding have little clinical relevance. Clin Pharmacol Ther 71: 115-121.[CrossRef][Medline]

Chen J and Hage DS (2004) Quantitative analysis of allosteric drug-protein binding by biointeraction chromatography. Nat Biotechnol 22: 1445-1448.[Medline]

Crichton RR and Ward RJ (2003) An overview of iron metabolism: molecular and cellular criteria for the selection of iron chelators. Curr Med Chem 10: 997-1004.[Medline]

Galanello R, Piga A, Alberti D, Rouan MC, Bigler H, and Sechaud R (2003) Safety, tolerability and pharmacokinetics of ICL670, a new orally active iron-chelating agent in patients with transfusion-dependent iron overload due to beta-thalassemia. J Clin Pharmacol 43: 565-572.[Abstract/Free Full Text]

Ghuman J, Zunszain PA, Petitpas I, Bhattacharya AA, Otagiri M, and Curry S (2005) Structural basis of the drug-binding specificity of human serum albumin. J Mol Biol 353: 38-52.[CrossRef][Medline]

Hershko C, Link G, and Cabantchik I (1998) Pathophysiology of iron overload. Ann NY Acad Sci 850: 191-201.[CrossRef][Medline]

Hinderling PH (1997) Red blood cells: a neglected compartment in pharmacokinetics and pharmacodynamics. Pharmacol Rev 49: 279-295.[Abstract/Free Full Text]

Nick H, Acklin P, Lattmann R, Buehlmayer P, Hauffe S, Schupp J, and Alberti D (2003) Development of tridentate iron chelators: from desferrithiocin to ICL670. Curr Med Chem 10: 1065-1076.[CrossRef][Medline]

Nisbet-Brown E, Olivieri NF, Giardina PJ, Grady RW, Neufeld EJ, Sechaud R, Krebs-Brown AJ, Anderson JR, Alberti D, Sizer KC, et al. (2003) Effectiveness and safety of ICL670 in iron-loaded patients with thalassaemia: a randomised, double-blind, placebo-controlled, dose-escalation trial. Lancet 361: 1597-1602.[CrossRef][Medline]

Porter JB (2001) Deferoxamine pharmacokinetics. Semin Hematol 38: 63-68.[Medline]

Rolan PE (1994) Plasma protein binding displacement interactions—why are they still regarded as clinically important? Br J Clin Pharmacol 37: 125-128.[Medline]

Sansom LN and Evans AM (1995) What is the true clinical significance of plasma protein binding displacement interactions? Drug Saf 12: 227-233.[Medline]

Steinhauser S, Heinz U, Bartholoma M, Weyhermueller T, Nick H, and Hegetschweiler K (2004) Complex formation of ICL670 and related ligands with Fe(III) and Fe(II). Eur J Inorg Chem 2004: 4177-4192.

Sudlow G, Birkett DJ, and Wade DN (1976) Further characterization of specific drug binding sites on human serum albumin. Mol Pharmacol 12: 1052-1061.[Abstract/Free Full Text]


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