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Faculty of Pharmacy, University of Manitoba, Winnipeg, Manitoba, Canada
(Received March 31, 2008; Accepted May 29, 2008)
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Abstract |
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; Hasinoff et al., 1998; Cvetkovi
and Scott, 2005; Hasinoff and Herman, 2007) and has just been approved in the United States for the prevention of anthracycline-induced extravasation injury (Hasinoff, 2008). There is now considerable evidence to indicate that the cardiotoxicity of doxorubicin may be because of iron-dependent oxygen free radical formation (Malisza and Hasinoff, 1995; Meyers, 1998; Hasinoff and Herman, 2007) on the relatively unprotected cardiac muscle. Dexrazoxane may act through its metal-chelating rings-opened hydrolysis product ADR-925 (Fig. 1), which can either remove iron from the iron-doxorubicin complex (Buss and Hasinoff, 1993) or bind free iron (Diop et al., 2000), thus preventing iron-based oxygen radical formation. Thus, dexrazoxane can be considered a prodrug analog of EDTA that is activated on hydrolysis to its one-ring open intermediates B and C, and then to its fully rings-opened form ADR-925 according to the scheme in Fig. 1 (Hasinoff, 1990, 1994a,b, 1998; Hasinoff and Herman, 2007).
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) and in rats (Schroeder and Hasinoff, 2002). The rapid rate of hydrolysis of dexrazoxane and the rapid appearance of ADR-925 in plasma in vivo suggest that dexrazoxane first and then B and C are all enzymatically metabolized. We also showed that rats rapidly metabolized a mixture of B and C to ADR-925, which suggested that these metabolites were themselves enzymatically metabolized (Schroeder and Hasinoff, 2005). We have shown that pure dihydropyrimidinase (DHPase) (EC 3.5.2.2) enzymatically hydrolyzes dexrazoxane to B and C but cannot enzymatically hydrolyze B and C to ADR-925 (Hasinoff et al., 1991; Hasinoff, 1993). We have also shown that another zinc hydrolase, dihydroorotase (DHOase) (EC 3.5.2.3
[EC]
), is able to enzymatically hydrolyze B and C to ADR-925 but does not act on dexrazoxane (Schroeder and Hasinoff, 2002). Thus, it is hypothesized that DHPase and DHOase act sequentially and in concert to effect the full metabolism of dexrazoxane to its active metal ion-chelating form ADR-925. We also previously showed that B and C are rapidly formed from dexrazoxane in a primary rat hepatocyte suspension (Schroeder et al., 2005), which was consistent with dexrazoxane being metabolized by DHPase. We also showed that C underwent DHOase-catalyzed metabolism in a myocyte suspension (Schroeder et al., 2005). DHOase is present in a variety of tissues including the heart, liver, and kidney (Kennedy, 1974) and in erythrocytes and leukocytes (Smith and Baker, 1959). However, although DHPase is present in the liver and the kidney, it is not present in the heart (Dudley et al., 1974; Hasinoff et al., 1991; Hamajima et al., 1996). To determine the importance of DHOase-mediated metabolism of dexrazoxane, the metabolism of dexrazoxane and B and C was studied in rats that had been pretreated with the potent DHOase inhibitor 5-aminoorotic acid (Christopherson and Jones, 1980).
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Materials and Methods |
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). Errors, where cited or plotted, are the S.E.M.
Analysis of B, C, and ADR-925. The HPLC analysis of dexrazoxane, B, and C using an ion-pair reagent with the reversed-phase C18 column (detection wavelength 205 nm) has been described (Schroeder et al., 2002, 2003; Schroeder and Hasinoff, 2005). ADR-925 was determined on a BMG (Durham, NC) Fluostar Galaxy 96-well fluorescence plate reader (
ex 485 nm, em 520 nm) using the calcein fluorescence assay method we previously described (Schroeder and Hasinoff, 2005). The limit of quantitation for dexrazoxane, B, C, and ADR-925 in plasma was 0.5, 1, 1, and 10 µM, respectively.
DHPase-Catalyzed Biosynthesis of the B/C Mixture. Milligram quantities of the B/C mixture were biosynthesized using DHPase as we previously described (Schroeder and Hasinoff, 2005). DHPase rapidly hydrolyzes dexrazoxane to B and C but not to ADR-925 (Hasinoff et al., 1991; Hasinoff, 1993; Schroeder and Hasinoff, 2005). Dexrazoxane and ADR-925 levels in the treatment mixture were less than 0.03 and 0.1 mol %, respectively, of the initial dexrazoxane concentration. Under these reaction conditions, dexrazoxane was hydrolyzed to B and C with a B/C ratio of 4.1:1, which is consistent with previous published enzyme kinetic reports of DHPase-mediated hydrolysis of dexrazoxane (Hasinoff, 1993; Schroeder and Hasinoff, 2005). Because of the amounts of B and C required for the rat studies, it was not practical to separate the chemically very similar B and C (Fig. 1).
Dosing and Sample Collection. Treatment of the rats (male Sprague-Dawley, 300–350 g) with the drugs, blood sampling, and sample handling were done as previously described (Schroeder and Hasinoff, 2005). A 10-mg/ml solution of 5-aminoorotic acid was prepared just before use in sterile saline (0.9% NaCl, w/v) by adding NaOH to dissolve it, and it was then titrated to pH 7 and stored at 37°C until used. The 5-aminoorotic acid–treated rats were treated with an i.v. bolus infusion (2 ml/min) through the tail vein with 5-aminoorotic acid (20 mg/kg) 5 min before treatment with either dexrazoxane hydrochloride (40 mg/kg) or the B/C (20 mg/kg) mixture. The animal protocol was approved by the University of Manitoba Animal Care Committee.
ADR-925 Levels in Heart and Liver Homogenates. After the last blood collection time point (2–2.5 h) after the infusion of dexrazoxane, or 1.5 h after the infusion of the B/C mixture, the heart and liver were removed, weighed, and treated as previously described (Schroeder and Hasinoff, 2005). Using surgical scissors, the organs were cut into small pieces (<5 mm3), washed three times in a 50-ml centrifuge tube by adding 30 ml of 10 mM HCl to stabilize dexrazoxane and B and C (Hasinoff, 1994a), and rapidly swirled for about 1 min after which the wash solution was discarded. After the third wash the wash solution was visibly clear of blood. The washed minced organs were homogenized using a Polytron homogenizer (Kinematica GmbH, Basel, Switzerland) for 5 min. The homogenate was centrifuged at 0°C for 2 h at 18,000g to remove HCl-denatured protein. The supernatant was removed and stored at –80°C until analyzed.
Myocyte Isolation and Culture. Ventricular myocytes were isolated from 1- to 3-day-old Sprague-Dawley rats as we have described (Hasinoff et al., 2003a, 2007; Schroeder et al., 2005). Briefly, minced ventricles were serially digested with collagenase and trypsin in phosphate-buffered saline/1% (wt/v) glucose at 37°C in the presence of DNase and preplated for 1 h in large Petri dishes to deplete fibroblasts that preferentially attach. Collagenase, trypsin, and deoxyribonuclease were obtained from Worthington Biochemicals (Freehold, NJ). For the lactate dehydrogenase (LDH) release experiments, the myocyte-rich supernatant was plated at high density on day 0 in 24-well plastic culture dishes (5 x 105 myocytes/well, 750 µl/well). The preparation, which was typically greater than 90% viable by trypan blue exclusion, yielded an almost confluent layer of uniformly beating heart myocytes by day 2. After addition of drug to the cell suspensions, samples were removed at the times indicated.
LDH Release Assay. LDH released into the myocyte growth medium was determined as previously described (Hasinoff et al., 2003a, 2007). For the 5-aminoorotic acid treatments, the myocytes were pretreated with 5-aminoorotic acid (100 µM) for 1 h, then treated with dexrazoxane for 3 h, and then with doxorubicin (1.6 µM) for 3 h. At the end of the doxorubicin treatment period, the myocytes were washed twice with (and replaced with) medium containing 5-aminoorotic acid (100 µM) and dexrazoxane. Starting on day 6 after plating, samples (80 µl) of the myocyte supernatant were collected every 24 h for 3 days after treatment, and the samples were frozen at –80°C and analyzed within 1 week. After the last supernatant sample was taken, the myocytes were lysed with 250 µl of 1% (v/v) Triton X-100/2 mM EDTA/0.1 M phosphate buffer, pH 7.8, for 20 min at room temperature. The total cellular LDH activity, from which the percentage of LDH was calculated, was determined from the activity of the lysate plus the activity of three 80-µl samples previously taken. The LDH activity was determined in quadruplicate in a kinetic assay in 96-well plate in a Molecular Devices (Sunnyvale, CA) plate reader as previously described (Hasinoff et al., 2003a, 2007). The initial velocity of the LDH-catalyzed reaction of NAD+ with lactate to produce NADH and pyruvate was determined at 340 nm at 25°C. The assay buffer contained 2.4 mM NAD+ and 290 mM sodium lactate in 28 mM Tris buffer, pH 8.8. Where significance is indicated, an unpaired t test was used.
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Results |
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The concentration-time dexrazoxane plasma levels shown in Fig. 2A for rats treated with dexrazoxane only (Fig. 2A) are similar to those previously obtained (Hasinoff and Aoyama, 1999a; Schroeder and Hasinoff, 2002). The plasma concentration of dexrazoxane at 5 min for rats treated with 5-aminoorotic acid before dexrazoxane treatment was 515 ± 38, which is close to the value of 529 ± 41 µM for dexrazoxane alone. Also, the AUC5–120 of dexrazoxane for rats pretreated with 5-aminoorotic acid was not significantly different (p > 0.5) compared with rats treated with dexrazoxane alone (15,100 ± 970 µM · min compared with 18,600 ± 1200 µM · min, respectively), which indicated that 5-aminoorotic acid did not change the elimination kinetics of dexrazoxane, and thus the decrease in the ADR-925 AUC5–120 values was not because of 5-aminoorotic acid–mediated changes in the systemic clearance of dexrazoxane.
The intermediates B and C were both maximally observed in plasma at the earliest measured time point (5 min) (Fig. 2B). Pretreatment with 5-aminoorotic acid did not significantly change (p > 0.2) the plasma concentrations of either B or C at 5 min. After dexrazoxane administration, the B and C levels both rapidly decreased. The concentration of C fell below the limit of detection, at times greater than 15 min for the 5-aminoorotic acid pretreatment. For the dexrazoxane-alone treatment, low but detectable levels of C were observable up to 120 min. Detectable levels of B, with and without 5-aminoorotic acid pretreatment, were observed up to 120 min. Levels of B with the 5-aminoorotic acid pretreatment were above those compared with dexrazoxane-alone treatment up to about 45 min, after which they were both approximately the same. The fact that after dexrazoxane treatment the levels of B and C did not change with 5-aminoorotic acid pretreatment (but that of their ADR-925 metabolite did) suggests that DHPase-mediated formation of B and C and nonmetabolic routes of elimination to ADR-925 are rate-determining processes for these two intermediate metabolites. Also the fact that ADR-925 levels in 5-aminoorotic acid–treated and untreated rats are not significantly different up to 30 min and are only different thereafter also suggests that the DHOase-mediated conversion of B and C into ADR-925 is a slower process than the first step (Fig. 1). Because of the size and charge state of B and C, it is also likely that urinary clearance also contributes to the systemic elimination of B and C. Thus, it is not surprising that the systemic impact of enzymatic hydrolysis (metabolic clearance) is masked by this.
As shown in Fig. 2A, ADR-925 was seen in the plasma of rats pretreated or not with 5-aminoorotic acid before treatment with dexrazoxane. However, pretreatment with 5-aminoorotic acid had a large effect on the plasma levels of ADR-925. The AUC5–120 values for ADR-925 in rats pretreated with 5-aminoorotic acid was 5.3-fold lower (p < 0.001) compared with rats treated with dexrazoxane alone (940 ± 240 µM · min compared with 4980 ± 460 to µM · min, respectively). Thus, these results indicate that 5-aminoorotic acid pretreatment strongly inhibited the appearance of ADR-925 in the plasma.
Effect of Pretreatment with 5-Aminoorotic Acid before a B/C Mixture Treatment on B and C Elimination and ADR-925 Formation. The concentration-time plasma levels of B, C, and ADR-925 of rats treated with a B/C mixture, with and without a 5-aminoorotic acid pretreatment, are given in Fig. 3, A and B. The data were fit to a one-compartment pharmacokinetic model because a two-compartment model was judged inappropriate based on Akaike's information criterion estimated from WinNonlin. The Cmax for B (Fig. 3A) for rats pretreated with 5-aminoorotic acid before treatment with a B/C mixture rats was not significantly different (p = 0.9) compared with rats treated with a B/C mixture alone (427 ± 111 µM compared with 420 ± 81 µM, respectively). Both B and C initially rapidly decreased similarly in concentration with or without pretreatment with 5-aminoorotic acid, but levels of B appeared to be prolonged with the 5-aminoorotic acid pretreatment. Likewise, the half-life for B for rats pretreated with 5-aminoorotic acid before treatment with a B/C mixture was not significantly different (p = 0.6) compared with rats treated with the B/C mixture alone (5.8 ± 2.9 compared with 4.8 ± 1.0 min, respectively). The fact that the pharmacokinetic parameters Cmax and the half-life for elimination of B and C were unchanged when rats were pretreated with 5-aminoorotic acid before treatment with the B/C mixture compared with rats treated with the B/C mixture alone indicated that 5-aminoorotic acid did not change the elimination kinetics of B and C, and thus the decrease in the ADR-925 Cmax value was not the result of 5-aminoorotic acid–mediated changes in the elimination of B and C.
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The ratio of the average values of B and C (414 ± 33 and 66 ± 13 µM, respectively) observed at 2 min of 6.3 ± 1.4 can be compared with the ratio of 4.4 in the infusion mixture. Because of the lower concentration of C in the mixture and its rapid decrease to below quantifiable limits, it was not possible to carry out further analysis of the data for C.
As can be seen from the data in Fig. 3B, ADR-925 rapidly appeared in plasma at its maximally observed concentration at the first time point of 2 min and then decreased with time. The Cmax for ADR-925 for rats pretreated with 5-aminoorotic acid before treatment with a B/C mixture was significantly decreased (p = 0.018) compared with rats treated with a B/C mixture alone (49 ± 2 µM compared with 137 ± 38 µM, respectively). Whereas the half-life for ADR-925 for rats pretreated with 5-aminoorotic acid before treatment with a B/C mixture rats did increase, the increase was not quite significant (p = 0.053) compared with rats treated with a B/C mixture alone (25 ± 9 min compared with 9 ± 4 min, respectively). Also, the plasma level of ADR-925 in either treatment group was not significantly different at 1.5 h (p = 0.4).
Effect on ADR-925 Tissue Levels of Pretreatment with the DHOase Inhibitor 5-Aminoorotic Acid before Treatment with Dexrazoxane or the B/C Mixture. ADR-925 levels in the 18,000g supernatant fraction of heart and liver tissue homogenates of rats treated with 5-aminoorotic acid before treatment with dexrazoxane (40 mg/kg) or treatment with the B/C mixture (20 mg/kg) are shown in Table 1. When the dexrazoxane-treated rats were pretreated with 5-aminoorotic acid, ADR-925 levels in both the heart and the liver were significantly reduced (5.3- and 9.7-fold, p < 0.001 and 0.005, respectively). In contrast, however, when the B/C mixture-treated rats were pretreated with 5-aminoorotic acid, the ADR-925 levels in neither the heart nor the liver were significantly reduced (p = 0.7 and 0.5, respectively). In the case of the dexrazoxane treatment, these results showed that 5-aminoorotic acid greatly inhibited the conversion of B and C to ADR-925, resulting in reduced heart and tissue levels. It is not known how quickly 5-aminoorotic acid is distributed in the heart and liver (and other) tissues that contain DHOase and whether inhibitory levels of 5-aminoorotic acid are achieved in DHOase-containing tissues. The values we obtained can be compared with total 14C-labeled dexrazoxane levels determined at 5 min of 320 and 640 µmol/kg in heart and liver, respectively, for mice administered 100 mg/kg dexrazoxane (Mhatre et al., 1982).
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Effect of 5-Aminoorotic Acid on Dexrazoxane-Mediated Protection from Doxorubicin-Induced LDH Release in Myocytes. LDH release is a widely used measure of drug-induced damage to myocytes (Adderley and Fitzgerald, 1999; Hasinoff et al., 2003a, 2007). Using the LDH release assay, we examined the ability of 5-aminoorotic acid to inhibit dexrazoxane-mediated protection from doxorubicin-induced LDH release to determine whether inhibition of DHOase reduced the ability of dexrazoxane to protect myocytes from doxorubicin-induced damage. As shown in Fig. 4, A and B, 5, 20, and 100 µM dexrazoxane significantly reduced LDH release in a concentration-dependent manner from myocytes (p = 0.021, 0.004, and <0.001 at 24 h, and p = 0.008, 0.003, and <0.001 at 72 h, respectively) from doxorubicin-induced LDH release. Doxorubicin significantly increased LDH release compared with untreated control myocytes (p < 0.001) at both times. Pretreatment of myocytes with 5-aminoorotic acid compared with untreated control myocytes did not significantly affect LDH release. Pretreatment of myocytes with 5-aminoorotic acid did not significantly affect the ability of dexrazoxane to protect myocytes from doxorubicin-induced LDH release at both 24 and 72 h.
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) and in the rat (Hasinoff and Aoyama, 1999a,b; Schroeder and Hasinoff, 2005) showed that B, C, and ADR-925 quickly appeared in the plasma after i.v. administration, a result which suggested that dexrazoxane, B, and C were enzymatically metabolized to ADR-925. We previously showed (Schroeder et al., 2002) using purified DHOase that 5-aminoorotic acid, which is a strong inhibitor of DHOase with an inhibition constant Ki of 6 µM (Christopherson and Jones, 1980), inhibited the DHOase-catalyzed hydrolysis of C. The large and significant decreases in ADR-925 plasma AUC5–120 values and plasma levels (Fig. 2B) in rats pretreated with 5-aminoorotic acid before dexrazoxane treatment, relative to rats not treated, indicated that DHOase played a major role in the overall metabolism of dexrazoxane to ADR-925.
Effect of DHOase Inhibition on B/C Metabolism to ADR-925. The initial plasma levels (apparent Cmax) of ADR-925 were significantly decreased (Fig. 3B) when rats were pretreated with 5-aminoorotic acid before treatment with the B/C mixture compared with rats treated with the B/C mixture alone. This result also supports the conclusion that DHOase is important in the metabolism of B and C. The rapid appearance of ADR-925 is likely because of a combination of DHOase-mediated enzymatic hydrolysis in tissue, chemical instability, and Ca2+- and Mg2+-promoted conversion to ADR-925 by these metal ions present in plasma (Buss and Hasinoff, 1997; Schroeder et al., 2005). In rat blood, hydrolysis of C occurs with a half-life of about 50 min (Schroeder et al., 2005). Thus, the lack of effect on Cmax is most likely caused by the chemical instability of B and C in plasma. Blood and plasma stability experiments showed that whereas dexrazoxane is stable (t1/2 > 300 min), C is not (t1/2 50 min) (Schroeder et al., 2005). This, at least in part, provides an explanation as to why no measurable inhibitory effect on the systemic appearance of ADR-925 was seen following treatment with B/C. Thus, presumably once B/C is in the systemic circulation, the primary route of clearance would be through chemical hydrolysis. In the tissues we anticipate that the primary route of clearance of B and C would be through enzymatic hydrolysis. This blood instability would also be a primary route of systemic elimination for the B/C mixture once these metabolites diffuse into the systemic circulation.
Effect on ADR-925 Tissue Levels of Pretreatment with the DHOase Inhibitor 5-Aminoorotic Acid before Treatment with Dexrazoxane or the B/C Mixture. Because the liver contains both DHPase and DHOase, which can act sequentially to form ADR-925, it is not unexpected that this tissue would contain ADR-925 (Table 1) (Schroeder and Hasinoff, 2005). However, the fact that ADR-925 is found in the heart (which does not contain DHPase) (Hamajima et al., 1996) either when treated with dexrazoxane or the B/C mixture suggests that B and C formed in the liver are taken up by the heart and metabolized there. In support of this conclusion we showed that isolated neonatal rat myocytes were able to take up B, C, and ADR-925 and displace iron from an intracellular fluorescence-quenched iron-calcein complex (Hasinoff et al., 2003b).
Pretreatment with 5-aminoorotic acid caused a large and significant decrease of ADR-925 heart and liver tissue levels in dexrazoxane-treated rats. The dexrazoxane results are consistent with the DHOase inhibitor 5-aminoorotic acid partially inhibiting the conversion of B and C to ADR-925, resulting in reduced heart and liver tissue levels. It is, however, unknown how quickly 5-aminoorotic acid is distributed in the heart and liver (and other) tissues that contain DHOase, and thus whether inhibitory levels of 5-aminoorotic acid were achieved in DHOase-containing tissues.
In the case where rats were treated with the B/C mixture, it is unclear why the heart and liver tissue levels of ADR-925 were not affected by the 5-aminoorotic acid pretreatment. The reason cannot be that 5-aminoorotic acid did not enter the tissue because we showed that 5-aminoorotic acid inhibited the metabolism of C in both myocyte and hepatocyte suspensions (Schroeder et al., 2005). From the data of Fig. 3B it can be seen that at 1.5 h, when the tissues were collected, the plasma levels of ADR-925 were not significantly different in either treatment group. Thus, it is perhaps not surprising that the tissue levels may also have achieved equal levels. Neutral dexrazoxane also may have been distributed into the tissues more completely and quickly than the anionic and presumably less permeable B and C. If this were the case, the metabolism of B and C in heart and liver tissues would be less important.
Pretreatment of Myocytes with 5-Aminoorotic Acid Did Not Significantly Affect the Ability of Dexrazoxane to Protect Myocytes from Doxorubicin-Induced LDH Release. The results shown in Fig. 4, A and B, show that inhibiting the DHOase-mediated metabolism of B and C in myocytes did not affect the ability of dexrazoxane to protect myocytes from doxorubicin-induced damage. We know that 5-aminoorotic acid enters myocytes because we previously showed that 5-aminoorotic acid inhibits the hydrolysis of C and dihydroorotic acid, the natural substrate of DHOase (Schroeder et al., 2005), in a myocyte suspension. The Dulbecco's modified Eagle's medium/F-12 myocyte culture medium contains 1.0 mM Ca2+ and 0.9 mM Mg2+. Thus, the lack of an effect may be because in the medium B and C also undergo a Ca2+- and Mg2+-promoted conversion (t1/2 
0.9 h) to ADR-925 (Buss and Hasinoff, 1997; Schroeder et al., 2005) and also a slow (t1/2 5.7 h) nonenzymatic base-catalyzed conversion to ADR-925 (Hasinoff, 1994a,b). Thus, in myocytes at least, the DHOase enzymatic pathway that yields ADR-925 (Schroeder et al., 2002) may not be critical for the activation to ADR-925. A second, although less likely, reason that 5-aminoorotic acid does not reduce the ability of dexrazoxane to protect myocytes from doxorubicin-induced damage is that dexrazoxane is cardioprotective, not through its metal-chelating hydrolysis product ADR-925, but is protective through its ability to inhibit topoisomerase II (Hasinoff and Herman, 2007). Dexrazoxane is a strong inhibitor (IC50 10 µM) of the catalytic activity of DNA topoisomerase II (Hasinoff et al., 1995), an enzyme which catalyzes DNA strand passage events (Fortune and Osheroff, 2000). Although it is possible that the cardioprotective and extravasation protective effects of dexrazoxane may be because of its ability to inhibit topoisomerase II, it is difficult to envision a mechanism by which this would occur as these tissues are not rapidly proliferating and contain only low levels of topoisomerase II
.
The pharmacokinetics of the metabolism of dexrazoxane to B and C and then to ADR-925 in the rat model allometrically scales well to that seen in humans (Schroeder et al., 2003; Schroeder and Hasinoff, 2005); thus, it would appear that the kinetics of the metabolism in the two species is similar. In conclusion, these studies showed that the metabolism of dexrazoxane to its presumably active metal-chelating form ADR-925 in the rat was strongly inhibited by pretreatment with the DHOase inhibitor 5-aminoorotic acid. The metabolism of the one-ring open metabolites B and C were likewise inhibited in the rat by 5-aminoorotic acid pretreatment. The tissue levels of ADR-925 in the heart and the liver after dexrazoxane treatment were both strongly affected by pretreatment with 5-aminoorotic acid. Therefore, it can be concluded that the enzyme DHOase, which is present in both the heart and liver, is largely responsible for the metabolism of the B and C metabolites of dexrazoxane. Thus, these results provide a mechanistic basis for the antioxidant cardioprotective activity of dexrazoxane.
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Footnotes |
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
ABBREVIATIONS: ADR-925, N,N'-[(1S)-1-methyl-1,2-ethanediyl]bis[(N-(2-amino-2-oxoethyl)]glycine; B, N-(2-amino-2-oxoethyl)-N-[(1S)-2-(3,5-dioxo-1-piperazinyl)-1-methylethyl]glycine; C, N-(2-amino-2-oxoethyl)-N-[(2S)-2-(3,5-dioxo-1-piperazinyl)propyl]glycine; DHPase, dihydropyrimidine amidohydrolase or dihydropyrimidinase; DHOase, dihydroorotase; HPLC, high-pressure liquid chromatography; LDH, lactate dehydrogenase; AUC5–120, area-under-the-curve of concentration-time data for dexrazoxane or ADR-925 from 5 to 120 min.
Address correspondence to: Brian B. Hasinoff, Faculty of Pharmacy, University of Manitoba, Winnipeg, Manitoba R3T 2N2, Canada. E-mail: b_hasinoff{at}umanitoba.ca
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RS and Scott LJ (2005) Dexrazoxane: a review of its use for cardioprotection during anthracycline chemotherapy. Drugs 65: 1005–1024.[CrossRef][Medline]This article has been cited by other articles:
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  B. B. Hasinoff, D. Patel, and K. A. O'Hara Mechanisms of Myocyte Cytotoxicity Induced by the Multiple Receptor Tyrosine Kinase Inhibitor Sunitinib Mol. Pharmacol., December 1, 2008; 74(6): 1722 - 1728. [Abstract] [Full Text] [PDF]
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) and ADR-925 (
) for rats pretreated with 5-aminoorotic acid (20 mg/kg) 5 min before treatment with dexrazoxane (40 mg/kg) (n = 3) compared with average plasma concentrations of dexrazoxane (
) and ADR-925 (
) and C (
) for rats pretreated with 5-aminoorotic acid (20 mg/kg) 5 min before treatment with dexrazoxane (40 mg/kg) compared with average plasma concentrations of B (
) and C (
) for rats treated with dexrazoxane (40 mg/kg) alone.
