Journal of Pharmaceutical Investigation (2013) 43:243–249 DOI 10.1007/s40005-013-0076-1
RESEARCH ARTICLE
Validation of high-performance liqid chromatography method to determine epirubicin and its pharmacokinetics after intravenous bolus administration in rats Dae Hwan Shin • Seong Hyeok Park • Oh-Seung Kwon Chun-Woong Park • Kun Han • Youn Bok Chung
•
Received: 7 April 2013 / Accepted: 1 May 2013 / Published online: 25 May 2013 Ó The Korean Society of Pharmaceutical Sciences and Technology 2013
Abstract We investigated the pharmacokinetics of epirubicin, an anthracycline derivative antibiotics, after intravenous (i.v.) bolus administration in rats. To analyze epirubicin levels in the plasma, bile, urine and tissue samples, we developed an high-performance liqid chromatography (HPLC)-based method which was validated for a pharmacokinetic study by suitable criteria. The plasma concentration of epirubicin after i.v. bolus administration was rapidly disappeared within 10 min from the blood circulation. The mean plasma half-lives at a phase (t1/2a) when administered at the dose of 2, 5, 10, 25 and 50 mg/kg were 2.14–2.61 min. The values of t1/2b at the corresponding doses increased two folds (from 150 to 291 min) with increasing doses. The CLt values significantly decreased with the increase in dose. In contrast, Vdss values increased about 1.5 times with the increase in dose from 2 to 50 mg/kg. Of the various tissues, epirubicin mainly distributed to the kidney, lung, heart and liver after i.v. bolus administration. The epirubicin concentrations in various tissues at 24 h after i.v. bolus administration were below 1.0 lg/g tissue. Epirubicin was excreted largely in the bile after i.v. bolus administration at the dose of 2, 10 and 50 mg/kg. The cumulative amount of epirubicin in the urine 72 h after dosage represented 20 % of the amount excreted in the bile 12 h after high dosage, indicating that
D. H. Shin S. H. Park C.-W. Park K. Han Y. B. Chung (&) College of Pharmacy, Chungbuk National University, Chungbuk, Cheongju 361-763, South Korea e-mail:
[email protected] O.-S. Kwon Korea Institute of Science and Technology, Seoul 136-790, South Korea e-mail:
[email protected]
i.v. administered epirubicin was mainly excreted in the bile. In conclusion, epirubicin was rapidly cleared from the blood circulation and transferred to tissues such as the kidney and liver 2 h after i.v. bolus administration. Moreover, the majority of epirubicin appears to be excreted in the bile by 12 h after i.v. bolus administration. Keywords Epirubicin Pharmacokinetics HPLC Distribution Excretion
Introduction Anthracycline antibiotics are a class of drugs used in cancer chemotherapy derived from Streptomyces bacteria, specifically, Streptomyces peucetius var. caesius (Madduri et al. 1998; Arcamone 1998). These compounds are used to treat a wide range of cancers, including leukemias, lymphomas, breast, uterine, ovarian and lung cancers (Arcamone et al. 1969; Oki et al. 1979). The anthracyclines are some of the most effective anticancer treatments ever developed and are effective against more types of cancer than any other class of chemotherapy agents (Minotti et al. 2004; Peng et al. 1993). Their main adverse effect is cardiotoxicity, which considerably limits their usefulness. Other adverse effects include vomiting. The first anthracycline discovered was daunorubicin, trade name Daunomycin, which is produced naturally by Streptomyces peucetius, a species of actinobacteria. Doxorubicin (Adriamycin) was developed shortly after, and many other related compounds have followed, although few are in clinical use (Weiss 1992). Epirubicin is an anthracycline drug used for chemotherapy. It is marketed by Pfizer under the trade name Ellence in the USA and Pharmorubicin or Epirubicin
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Ebewe elsewhere. Similarly to other anthracyclines, epirubicin acts by intercalating DNA strands. Intercalation results in complex formation which inhibits DNA and RNA synthesis. It also triggers DNA cleavage by topoisomerase II, resulting in mechanisms that lead to cell death. Binding to cell membranes and plasma proteins may be involved in the compound’s cytotoxic effects. Epirubicin also generates free radicals that cause cell and DNA damage (Liang et al. 2007). Epirubicin is favoured over doxorubicin, the most popular anthracycline, in some chemotherapy regimens as it appears to cause fewer side-effects (Berchem et al. 1996; Robert 1993). Epirubicin has a different spatial orientation of the hydroxyl group at the 40 carbon of the sugar, which may account for its faster elimination and reduced toxicity (Fig. 1). Epirubicin is primarily used against breast and ovarian cancer, gastric cancer, lung cancer and lymphomas. The anti-tumor properties epirubicin are currently being investigated by clinical trials. Recent pharmacokinetic studies of epirubicin have been reported using the high performance liquid chromatography (HPLC)/mass spectrometry (MS) analysis (Maeda and Miwa 2013; Sottani et al. 2012). The studies were mainly focused on the plasma levels of the drug. However, accurate pharmacokinetic analyses of epirubicin have not yet been reported. We, therefore, have investigated the pharmacokinetics of epirubicin after intravenous (i.v.) bolus administration in rats. The pharmacokinetic parameters after its i.v. bolus administrations were determined. Furthermore, the elimination of epirubicin by the biliary and urinary systems and epirubicin tissue distribution were determined. To analyze epirubicin levels in biological samples, we used a simple HPLC-based method which has been developed and validated in our laboratory.
D. H. Shin et al.
Materials and methods Materials Epirubicin was obtained from Boryung Pharmaceutical Co. Ltd. (Korea). Solvents used in the epirubicin analysis were of HPLC grade and were filtered and degassed just prior to use. All other chemicals used in this study were of analytical reagent grade. Adult male Sprague–Dawley rats weighing 230–250 g (Sam Tac Co. Ltd., Kyunggi, Korea) were used for the pharmacokinetic studies. They were housed in individual metabolic cages during and after administration of epirubicin. The animals were maintained under a 12 h light/dark cycle with free access to water. HPLC analysis of epirubicin levels in biological samples Epirubicin levels were assayed by reverse phase HPLC on a Luna C18 column (Phenomenex, 4.6 mm 9 250 mm, 5 lm) that was interfaced with a Jasco HPLC system. This system consisted of a model PU-980 pump, a model AS-950-10 autoinjector, a model FP-2020 fluorescence detector, and a LC-Net II control borwin integrator (Jasco Co. Ltd., Japan). The mobile phase was a mixture of 0.02 M NaH2PO4 buffer and MeOH (38:62, v/v %). The flow rate was 0.7 ml/min. The epirubicin in elutes was monitored fluorometrically at an excitation wavelength (kex) of 480 nm and an emission wavelength (kem) of 550 nm. Sensitivity The lower limit of quantification (LOQ) was defined as the lowest concentration yielding a precision of less than 20 % (coefficients of variation, CV) and an accuracy of between 80 and 120 % of the theoretical value. Linearity
Fig. 1 Structural formula of epirubicin
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The linearity of the assay was assessed by preparing quality control samples containing epirubicin at concentrations ranging from 0.01 to 100 lg/ml (0.01, 0.05, 0.1, 0.5, 1, 5, 10, 50 and 100 lg/ml) and then plotting the actual versus the measured concentrations. The epirubicin samples were prepared in plasma, urine, bile and tissue homogenates. The resulting straight line regression equations were treated statistically (weighting factor: 1/concentration) and are presented with their correlation coefficients.
Validation of HPLC method to determine epirubicin and its pharmacokinetics
Precision and accuracy The precision and accuracy of the method were determined by preparing quality control samples, five for each of the epirubicin concentrations that range from 0.01 to 100 lg/ml, and then assaying these samples on the same day (repeatability) and on five consecutive days (reproducibility). Administration of epirubicin and analysis of its plasma levels Under light pentobarbital sodium anesthesia, the femoral vein and artery were cannulated with PE-50 polyethylene tubing (Intramedic, Clay Adams, USA.) for epirubicin administration and blood sampling, respectively. Epirubicin was administered into the femoral vein at the dose of 2, 5, 10, 25 and 50 mg/kg in rats. Blood was collected into heparinized tubes from the femoral artery 1, 2, 5, 10, 15, 30, 60, 120, 240 and 480 min after i.v. bolus administration. The blood samples were centrifuged for 15 min at 1,500 g and the plasma was harvested. Immediately after the collection of the plasma (100 ll) samples, daunorubicin (10 ll, 50 lg/ml) was added to each plasma test tube as an internal standard. Methanol (3 ml) was then added to precipitate the proteins and extract the compounds of interest. These mixtures were vortexed for 15 min and centrifuged for 15 min at 1,500 g. The supernatants were withdrawn, dried under a stream of dry nitrogen and reconstituted in 150 ll mobile phase for quantitative HPLC analyses. Analysis of biliary and urinary excretion of epirubicin Under light pentobarbital sodium anesthesia, the femoral vein was cannulated with PE-50 polyethylene tubing for epirubicin administration. A catheter (PE-10, Intramedic, Clay Adams, U.S.A.) was then implanted into the bile duct via a small abdominal incision. Blank bile was obtained just before the administration of 2 and 10 mg/kg epirubicin to three sets of rats via the femoral vein. Bile was collected 0–5, 5–10, 10–15, 15–30, 30–45, 45–60, 60–90, 90–120, 120–240, 240–480 and 480–720 min after the dose was administered. Urine was collected with the use of metabolic cages over the 72 h after epirubicin administration and stored at -70 °C until HPLC analysis. The epirubicin levels in the bile and urine were determined as described above.
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immediately removed, blotted onto filter papers, and weighed. The tissues were rinced in an ice-cold 50 mM tris–HCl buffer (containing 0.25 M sucrose, pH 7.4) and homogenized with a glass Potter–Elvehjem-type homogenizer with a Teflon pestle. After extracting 100 ll of 20 % homogenate with 3 ml methanol, the concentration of epirubicin in the supernatant was measured as described above. Pharmacokinetic analysis Epirubicin plasma concentration profiles after i.v. bolus administration were analyzed by fitting the data to the following biexponential equation according to the nonlinear least-squares method (MULTI) : Cp = Ae-at ? Be-bt. The pharmacokinetic parameters were subsequently calculated as follows: k21 = (Ab ? Ba)/(A ? B), kel = ab/k21, k12 = (a ? b)-(k21 ? kel), t1/2a = 0.693/a, and t1/2b = 0.693/b, where k12 and k21 represent the rate constants of transport between the central and peripheral compartments, respectively, kel represents the elimination rate constant, and t1/2a and t1/2b represent the plasma half lives at the a and b phases, respectively. Non-compartmental methods were also used to determine pharmacokinetic parameters. The area under the plasma concentration–time curve from time zero to infinity (AUC) was calculated from the equation AUC = AUCt ? Ct/b, where Ct is the last quantifiable concentration. The area under the plasma concentration– time curve from time zero to the time of the last quantifiable concentration (AUCt) was calculated by linear trapezoidal approximation. The following parameters were also calculated using the standard methods: the total plasma clearance (CLt) = Dose/AUC, the steady-state volume of distribution (Vdss) = CLtMRT, the mean residence time (MRT) = AUMC/AUC, where AUMC represents the area under the moment curve. Statistical analysis Two means were compared by the unpaired Student’s t test. One-way analysis of variance was used to test for significant differences between groups. Statistical significance was defined as p \ 0.05.
Results
Determination of the tissue distribution of epirubicin
Validation of the HPLC method
The rats were decapitated 2, 8 and 24 h after i.v. bolus administration of epirubicin at a dose of 10 mg/kg, respectively. The liver, kidney, lung, heart, small intestine, large intestine, stomach, thymus and muscle were
Figure 2 illustrates typical chromatogram of epirubicin and the internal standard (I.S.) in plasma. The chromatogram shows no peaks that interfere with the epirubicin and I.S. signals. To determine the linearity of the HPLC method,
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acceptance criteria were fulfilled for the within-day results, which demonstrate the repeatability of the method. The lower limit of quantification (LOQ) was, therefore, defined as 0.01 lg/ml. The mean absolute recovery of epirubicin was 96.8 %. Dose-dependent pharmacokinetics of epirubicin
quality control samples were prepared, five for each of nine epirubicn concentrations ranging from 0.01 to 100 lg/ml. These samples were assayed on the day of preparation and on the following four consecutive days. Mean regression equation was calculated from the resulting nine calibration curves. The mean regression equation was y = 0.215x 0.008 (r2 = 0.999), where y is the peak area ratio and x is the concentration. This equation shows significant linearity (p \ 0.01) over the concentration range of 0.01–100 lg/ ml. The mean regression equations for bile, urine and tissue homogenates were not significantly different from the equation for plasma. In between-day results, variations of both the precision and the accuracy were always \15 % (Table 1). The same Table 1 Precision and accuracy data for the determination of epirubicin in rat plasma (n = 5) Concentration (lg/ml)
Precision (%)
Accuracy (%)
Intra-day
Inter-day
Intra-day
0.01a
13.8
14.8
112.2
89.3
0.05
8.2
12.8
107.6
92.2
0.1
6.41
8.81
108.2
91.8
0.5
7.20
7.92
104.5
95.8
1
9.52
6.81
105.6
97.2
Inter-day
5
6.91
3.10
91.8
104.1
10 50
4.82 3.20
1.61 2.51
96.3 97.9
101.5 100.9
100
3.51
1.90
101.5
101.1
a
Limit of quantification (LOQ)
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Biliary and urinary excretion of epirubicin Figure 4 shows the cumulative amount of epirubicin excreted in the bile after i.v. bolus administration at the dose of 2, 10 and 50 mg/kg. Epirubicin was not detected in the bile 12 h after i.v. bolus administration. The cumulative
1000
Plasma Concentration (µg/ml)
Fig. 2 Representative chromatogram of epirubicin and internal standard (IS: daunorubicin) in plasma. The retention times of epirubicin and internal standard were 18.7 and 12.8 min, respectively. The chromatogram shows no peaks that interfere with the drug and IS signals
Figure 3 shows the concentrations of epirubicin over time in rat plasma after i.v. bolus administration at the dose of 2, 5, 10, 25 and 50 mg/kg. Epirubicin rapidly disappeared from the plasma by 10 min (a phase) after i.v. administration, followed by late disappearance in the b phase. The pharmacokinetic parameters of epirubicin after i.v. administration are summarized in Table 2. The mean plasma half-lives at a phase (t1/2a) when administered at the dose of 2, 5, 10, 25 and 50 mg/kg were 2.14, 2.15, 2.29, 2.56 and 2.61 min, respectively. The values of t1/2b at the corresponding doses increased two folds (from 150 to 291 min) with increasing doses. The pharmacokinetic parameters were also determined by non-compartmental methods. The CLt values significantly decreased with the increase in dose. In contrast, Vdss values increased about 1.5 times with the increase in dose from 2 to 50 mg/kg.
100
10
1
0.1
0.01 0
2
4
6
8
Time (hr) Fig. 3 Epirubicin concentration in rat plasma over time after i.v. bolus administration at the dose of 2 (Black circle), 5 (White circle), 10 (Inverted black triangle), 25 (Inverted white triangle) and 50 (Black box) mg/kg. Each point represents the mean ± S.E. of three rats
Validation of HPLC method to determine epirubicin and its pharmacokinetics
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Table 2 Pharmacokinetic parameters of epirubicin following i.v. bolus administration at the dose of 2, 5, 10, 25 and 50 mg/kg in rats Parameter
Dose 2 mg/kg
5 mg/kg
10 mg/kg
25 mg/kg
50 mg/kg
A
(lg/ml)
3.84
±0.18
10.6
±0.41
22.0
±2.30
45.5
±1.62
95.6
B
(lg/ml)
0.041
±0.012
0.093
±0.012
0.151
±0.022
0.543
±0.211
1.042
±0.363
a
(min-1)
0.324
±0.008
0.336
±0.034
0.317
±0.035
0.271
±0.012
0.271
±0.026
b
(min-1)
0.005
±0.001
0.004
±0.001
0.004
±0.001
0.004
±0.001
0.002
±0.001
k12
(min-1)
0.121
±0.009
0.124
±0.015
0.080
±0.024
0.115
±0.003
0.135
±0.008
k21
(min-1)
0.008
±0.002
0.007
±0.001
0.006
±0.001
0.007
±0.002
0.005
±0.001
k10 t1/2a
(min-1) (min)
0.201 2.14
±0.010 ±0.051
0.210 2.15
±0.020 ±0.220
0.202 2.29
±0.026 ±0.261
0.153 2.56
±0.012 ±0.120
0.133 2.61
±0.021 ±0.282
t1/2b
(min)
150
±24.6
156
±13.2
191
±8.65
208
±47.4
291
±28.8a
AUC
(lg min/ml)
19.5
±1.55
52.2
±4.03
115
±17.2
303
±14.5
765
±123
MRT
(min)
86.2
±16.5
87.2
±10.1
85.0
±24.1
132
±25.2
217
±6.77
Vdss
(l/kg)
8.79
±1.35
8.69
±1.52
7.77
±2.57
11.2
±2.54
15.0
±2.47a
AUMC
(mg min2/ml)
1.72
±0.447
4.47
±0.346
10.1
±3.25
39.2
±6.02
164.1
±20.7
68.4
±9.61a
CLt
(ml/min/kg)
104
±8.18
97.9
±7.43
93.0
±10.6
83.0
b
±3.93
±2.46
Each value represents the mean ± S.E. of three rats a
Significantly differently from the 2 mg/kg dose (p \ 0.01)
b
Significantly differently from the 2 mg/kg dose (p \ 0.05)
2.5
12
Cumulative amount (mg/kg)
Cumulative amount (mg/kg)
14
10 8 6 4 2
2.0
1.5
1.0
0.5
0.0
0 0
4
8
12
16
20
24
Time (hr)
0
12
24
36
48
60
72
Time (hr)
Fig. 4 Cumulative biliary excretion of epirubicin after i.v. bolus administration at the dose of 2 (Black circle), 10 (White circle) and 50 (Inverted black triangle) mg/kg. Each point represents the mean ± S.E. of three rats
Fig. 5 Cumulative urinary excretion of epirubicin after i.v. bolus administration at the dose of 2 (Black circle), 10 (White circle) and 50 (Inverted black triangle) mg/kg. Each point represents the mean ± S.E. of three rats
amount of epirubicin in the bile increased non-linearly as the dose was increased. The cumulative amounts of epirubicin in the bile 12 h after administering 2, 10 and 50 mg/kg were 0.559, 2.47 and 10.7 mg/kg, respectively. These values represent 27.9, 24.7 and 21.5 % of the epirubicin that was administered, respectively. The urinary excretion of epirubicin was maintained for up to 48 h after i.v. bolus administration at the dose of 2, 10 and
50 mg/kg (Fig. 5). The cumulative amounts of epirubicin in the urine 72 h after administering 2, 10 and 50 mg/kg were 0.151, 0.587 and 2.11 mg/kg, representing 7.57, 5.87 and 4.23 % of the epirubicin that was administered, respectively. The cumulative amount of epirubicin in the urine 72 h after dosage represented 20 % of the amount excreted in the bile 12 h after high dosage, indicating that i.v. administered epirubicin was mainly excreted in the bile.
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Tissue distribution of epirubicin The distribution of epirubicin in various tissues 2, 8 and 24 h after i.v. bolus administration of 10 mg/kg is described in Fig. 6. Epirubicin mainly distributed to the liver, kidney, lung and heart after i.v. bolus administration. Moreover, the epirubicin concentrations in the liver, kidney, lung and heart 2 h after i.v. administration (10 mg/kg) were approximately 10.7, 19.0, 10.6 and 14.8 lg/g tissue, respectively. These values were comparable to the concentration in the plasma shortly after i.v. bolus administration of 10 mg/kg (Fig. 3, Fig 6a). The epirubicin concentrations in various tissues 24 h after i.v. bolus administration were below 1 lg/g tissue (except kidney and liver) at the dose of 10 mg/kg Table 1.
Discussion The anti-tumor properties of epirubicin have been investigated in clinical trials by a number of pharmaceutical companies (Hong et al. 1994; Kim et al. 1996) and thus, determination of its pharmacokinetic characteristics will be highly useful. Consequently, we investigated the pharmacokinetics of epirubicin after i.v. bolus administration at a dose of 2–50 mg/kg. The CLt of epirubicin decreased following a dosage increase from 2 to 50 mg/kg. The clearance of epirubicin showed the nonlinear kinetics at the high doses of 25–50 mg/kg. Such a nonlinearity of the clearance of epirubicin might be attributable to the increase of Vdss following a dosage increase from 2 to 50 mg/kg (Table 2). In addition, the saturation in the elimination process in the hepatobiliary transport or urinary excretion may be one reason for the nonlinearity of the clearance of epirubicin. Our preliminary studies by isolated rat hepatocytes suggest
A
Concentration (µg/g)
20 10
B
20 10
0 12
24
F
20
12
24
G
10
0 12
24
12
12
24
0
H
20
0
24
12
I
20
12
24
12
24
J
20 10 0
0 0
0
24
10
0 0
10
0 0
E
20
10
10
0 0
D
20
0 0
20
10
C
20 10
0 0
that epirubicin is extensively uptaked into hepatocytes in a concentration dependent manner, and is uptaked via ATPdependent transporter (unpublished data). Anthracycline antibiotics, such as doxorubicin, ID-6105 and (200 R)-40 -O-tetrahydropyranyl adriamycin (THP) showed a rapid initial decrease in the blood concentration because of rapid transfer to tissues, and the tissue concentrations were maintained at high levels for a long time (Fujita et al. 1986; Yoo et al. 2005). Such a slow elimination of these drugs from body may be caused by their slow excretion to bile and urine (Fujita et al. 1986; Yoo et al. 2005). Aclacinomycin A, an anthracycline antibiotic, was also rapidly cleared from the blood and transferred to tissues, but low levels of the drug remained in the blood even 10 h after i.v. administration (Iguchi et al. 1980). Tissue levels of aclacinomycin A administered to mice were highest in the lungs and spleen. Higher distribution was also observed in the liver and kidney 2 h after administration of doxorubicin, ID-6105, THP, or aclacinomycin A (Fujita et al. 1986; Iguchi et al. 1980; Yoo et al. 2005). In the present study, epirubicin mainly distributed to the kidney and lung after i.v. bolus administration, as was observed with the other anthracycline antibiotics (Fig. 6). Epirubicin concentrations in the kidney or lung 2 h after i.v. bolus administration were comparable to the plasma concentration shortly after i.v. bolus administration (Fig. 3). The epirubicin concentrations in various tissues 24 h after i.v. bolus administration decreased to low levels (Fig. 6). Epirubicin was excreted largely in the bile after i.v. bolus administration. The amounts of epirubicin found in the bile by 12 h after the administration of 2, 10 and 50 mg/kg epirubicin were calculated to be 27.9, 24.7 and 21.5 % of the initial dose, respectively (Fig. 4). The corresponding values in the urine by 72 h after the administration of 2, 10 and 50 mg/kg epirubicin were 7.57, 5.87
0
12
24
0
12
24
Time (hr) Fig. 6 Epirubicin concentration in rat plasma (a), liver (b), kidney (c), lung (d), heart (e), small intestine (f), large intestine (g), stomach (h), thymus (i) and muscle (j) over time after i.v. bolus administration
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at the dose of 10 mg/kg. The plasma concentration–time curve in this figure a is the same data of 10 mg/kg dose in Fig. 3
Validation of HPLC method to determine epirubicin and its pharmacokinetics
and 4.23 % of the dose (Fig. 5), which were similar to values for aclacinomycin A and ID-6105 (Iguchi et al. 1980; Yoo et al. 2005). These results indicate that epirubicin is mostly excreted in the bile. However, the mechanism by which epirubicin is selectively excreted in the bile requires further study. In the present study, we developed and validated a simple HPLC method for the determination of epirubicin in the biological samples, such as plasma, bile, urine and tissue homogenates. However, we have failed to determine epirubicin in the feces by the method after i.v. bolus administration. The more accurate analysis methods may therefore be required to analyze the drug in the feces (Maeda and Miwa 2013).
Conclusion The HPLC analytical method for epirubicin developed in the present study is suitable for pharmacokinetic study. Our observation indicates that epirubicin was rapidly cleared from the blood circuration and transferred to tissues after i.v. bolus administration to rats. The clearance of epirubicin showed the nonlinear kinetics at the high doses of 25–50 mg/kg in rats. Epirubicin mainly distributed to the liver, kidney, lung and heart 2 h after i.v. bolus administration to rats. By 48 h after i.v. bolus administration, epirubicin concentrations in various tissues had decreased to very low levels. Moreover, the majority of epirubicin appears to be excreted in the bile. Acknowledgments This work was supported by the research Grant of the Chungbuk National University in 2011. DH Shin, SH Park, OS Kwon, CW Park, K Han and YB Chung declare that they have no conflicts of interest.
References Arcamone FM (1998) From the pigments of the actinomycetes to third generation antitumor anthracyclines. Biochimie 80:201– 206 Arcamone F, Cassinelli G, Fantini G, Grein A, Orezzi P, Pol C, Spalla C (1969) Adriamycin, 14-hydroxydaunomycin, a new antitumor antibiotic from S. peucetius var. caesius. Biotechnol Bioeng 11:1101–1110 Berchem GJ, Ries F, Hanfelt J, Duhem C, Keipes M, Delagardelle C, Dicato M (1996) Epirubicin cardiotoxicity: a study comparing low- with high-dose-intensity weekly schedules. Support Care Cancer 4:308–312
249
Fujita H, Ogawa K, Tone H, Iguchi H, Shomura T, Murata S (1986) Pharmacokinetics of doxorubicin, (200 R)-40 -O-tetrahydropyranyladriamycin and aclarubicin. Jpn J Antibiot 39:1321–1336 Hong YS, Hwang CK, Hong SK, Kim YH, Lee JJ (1994) Molecular cloning and characterization of the aklavinone 11-hydroxylase gene of Streptomyces peucetius subsp. caesius ATCC 27952. J Bacteriol 176:7096–7101 Iguchi H, Seryu Y, Kiyosaki T, Hori S, Tone H, Oki T (1980) Studies on the absorption, excretion and distribution of aclacinomycin A: absorption, excretion and distribution of 14C- or 3H-aclacinomycin A in mice, rats and rabbits. Jpn J Antibiot 33:169–178 Kim HS, Hong YS, Kim YH, Yoo OJ, Lee JJ (1996) New anthracycline metabolites produced by the aklavinone 11-hydroxylase gene in Streptomyces galilaeus ATCC 31133. J Antibiot 49:355–360 Liang CH, Shiu LY, Chang LC, Sheu HM, Kuo KW (2007) Solamargine upregulation of Fas, downregulation of HER2, and enhancement of cytotoxicity using epirubicin in NSCLC cells. Mol Nutr Food Res 51:999–1005 Madduri K, Kennedy J, Rivola G, Inventi-Solari A, Filippini S, Zanuso G, Colombo AL, Gewain KM, Occi JL, Macneil DJ, Hutchinson CR (1998) Production of the antitumor drug epirubicin (40 -epidoxorubicin) and its precursor by a genetically engineered strain of Streptomyces peucetius. Nat Biotechnol 16:69–74 Maeda S, Miwa Y (2013) Multicomponent high-performance liquid chromatography/tandem mass spectrometry analysis of ten chemotherapeutic drugs in wipe samples. J Chromatogr B Analyt Technol Biomed Life Sci 15:921–922 Minotti G, Menna P, Salvatorelli E, Cairo G, Gianni L (2004) Anthracyclines: molecular advances and pharmacologic developments in antitumor activity and cardiotoxicity. Pharmacol Rev 56:185–229 Oki T, Kitamura I, Matsuzawa Y, Shibamoto N, Ogasawara T, Yoshimoto A, Inui T, Naganawa H, Takeuchi T, Umezawa H (1979) Antitumor anthracycline antibiotics, aclacinomycin a and analogues II. Structural determination. J Antibiot 32:801–819 Peng X, Chen B, Lim CC, Sawyer DB (1993) The cardiotoxicology of anthracycline chemotherapeutics: translating molecular mechanism into preventative medicine. Mol Interv 5:163–171 Robert J (1993) Epirubicin. Clinical pharmacology and dose-effect relationship. Drugs 45(Suppl 2):20–30 Sottani C, Poggi G, Quaretti P, Regazzi M, Montagna B, Quaquarini E, Imbriani M, Leoni E, Di Cesare P, Riccardi A, Bernardo G, Minoia C (2012) Serum pharmacokinetics in patients treated with transarterial chemoembolization (TACE) using two types of epirubicin-loaded microspheres. Anticancer Res 32:1769–1774 Weiss RB (1992) The anthracyclines: will we ever find a better doxorubicin? Semin Oncol 19:670–686 Yoo BI, Ahan KB, Kang MH, Moon DC, Kwon OS, Lee HS, Ryu JS, Kim TY, Song S, Chung YB (2005) HPLC analysis and pharmacokinetic characteristics of 11-hydroxyaclacinomycin X (ID-6105), a novel anthracycline, in rats and beagle dogs. Biol Pharm Bull 28:688–693
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