PRECLINICAL DISTRIBUTION
Tissue Distribution
Following administration of IDAMYCIN®, its levels in plasma decline rapidly in a multiphasic manner with rapid distribution phases followed by a slower elimination phase. Tissue distribution studies 8 in CD-1 Swiss mice, bearing subcutaneously transplanted solid sarcomo 180 tumors, show that the observed area under the tissue concentration vs time curve (AUCt; C x t data) was higher in the kidney, lung, liver, small intestine and the sarcoma 180 tumor following IDAMYCIN dosing, compared to daunorubicin. Two-fold higher drug levels were achieved in the tumor tissue after IDAMYCIN than daunorubicin. However, no significant increase was observed in the heart tissue.(See Table 7.)
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TABLE 7: AUCt (TISSUE CONCENTRATION x t) AT 48 AND 72 HR FOLLOWING 12 mg/kg IV DOSE TO MICE IMPLANTED WITH SARCOMA 180
Time (hr)
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|
AUCt* (48) |
AUCt* (72) |
TISSUE |
Daunorubicin |
IDAMYCIN |
Ratio |
Daunorubicin |
IDAMYCIN |
Ratio |
Kidney |
37** |
63*** |
1.7 |
44 |
72 |
1.6 |
Liver |
24 |
31 |
1.3 |
25 |
35 |
1.4 |
Heart |
11 |
12 |
1.0 |
12 |
14 |
1.2 |
Spleen |
42 |
65 |
1.6 |
46 |
80 |
1.7 |
Tumor |
8 |
14 |
1.8 |
9 |
18 |
2.0 |
*AUCtIDA/AUCtDNR
**Rounded off to the nearest whole number. ***P < 0 05 v DNR.
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Comparative evaluation in rats has shown that clearance of radioactivity from tissues is much slower for IDAMYCIN relative to daunorubicin. This reflects a significantly prolonged retention of IDAMYCIN in tissues, which may provide greater cytotoxic exposure. Estimates of distribution volume indicate larger distribution volume for daunorubicin, but slower clearance of IDAMYCIN, suggesting longer retention Ithus enhanced exposure to cytotoxic components) in tissues.
Pharmacokinetic behavior of unchanged IDAMYCIN in various animal species used in toxicology and metabolism studies is shown in Table 8.
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TABLE 8: DISPOSITION PARAMETER ESTIMATES OF IDAMYCIN IN SEVERAL ANIMAL SPECIES[8,10]
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|
ESTIMATE |
PARAMETER |
MOUSE |
RAT |
RABBIT |
DOG |
Vdarea(L/kg) |
49.0 |
65.2 |
40.4 ± 1.9* |
23.0 ± 5.5 |
tΩ,Lamdaz |
23.6 |
9.9 |
2.8 ± 0.2** |
2.4 ± 0.3** |
CLp(mL/min/kg) |
24.0 |
76.0 |
275.0 ± 17.0 |
113.0 ± 19.9 |
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Abbreviations: Vdarea distribution volume; tΩ,Lamdaz, mean half if e; CLp, clearance parameters.
* Reported as Vd55 (steady state distribution volume).
**Values are reported as mean ± SEM. Values reported without SEM were derived from a series of pooled plasma samples, one per time point. |
Metabolism
IDAMYCIN® is extensively metabolized by hepatic reduction of the carboxyl function to idarubicinol, the 1 3-dihydro idarubicin, by mice, rats, and rabbits. In vitro studies in mice and rabbit cytosol aldoketoreductase demonstrate that daunorubicin undergoes faster metabolism and clearance compared to IDAMYCIN in most animals. This hepatic biotransformation is the predominant metabolic pathway, as supported by low recovery of unchanged drug in urine and bile[8,10] Other end products include polar metabolites and various aglycones, with idarubicinol representing the highest percentage of the dose (except in thin-layer chromatographic analysis of rat bile, where the polar fraction comprised the greatest percentage of dose).[10,32]
Excretion
Like other anthracyclines, IDAMYCIN is predominantly and slowly excreted via the biliary pathway in rats, rabbits, and dogs.[10,32]
Summary
IDAMYCIN features include rapid and extensive tissue distribution, slow excretion, biotransformation to idarubicinol and aglycone. Plasma drug levels decrease with a rapid initial and slow terminal phase. IDAMYCIN shows a substantially lower clearance than daunorubicin, leading to sustained IDAMYCIN (and idarubicinol) exposure in both animals and man. The findings in these species do not differ substantially from IDAMYCIN pharmacokinetics in humans.
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