Subchronic Toxicities of HZ1006, a Hydroxamate-Based Histone Deacetylase Inhibitor, in Beagle Dogs and Sprague-Dawley Rats
Abstract
:1. Introduction
2. Materials and Methods
2.1. Test Article
2.2. Animals
2.3. Doses and Treatment Plans
2.3.1. Subchronic Toxicity Test in Beagle Dogs
2.3.2. Subchronic Toxicity Test in SD Rats
2.4. Clinical Symptoms Observed on Dogs and Rats in Repeated Dose Toxicity Studies
2.5. Clinical Examination Parameters
2.5.1. Electrocardiogram (ECG)
2.5.2. Hematology
2.5.3. Serum Biochemistry
2.5.4. Urinalysis
2.5.5. Bone Marrow Examination
2.5.6. Histopathology
2.6. Toxicokinetics
2.7. Statistical Analysis
3. Results
3.1. Subchronic Toxicology Study in Dogs
3.1.1. Clinical Observation
3.1.2. Hematology
3.1.3. Clinical Chemistry
3.1.4. Urinalysis
3.1.5. ECG Parameters
3.1.6. Bone Marrow Examination
3.1.7. Necropsy
Gross Pathology and Organ Weights
Histopathological Findings
Male reproductive organs (testis, epididymis and prostate)
- Testis: The numbers of seminiferous tubules decreased in dogs belonging to the 80- and 40-mg/kg dose groups, while the tubule lumen decreased and had reduced numbers and types of spermatogenic cells when compared with the control group. Only spermatogonia and some primary and secondary spermatocytes were observed, and there were no mature sperm compared with the control group.
- Epididymis: When compared with the control group, there was a notable lack of mature sperm cells and secretions in the epididymal lumen, as well as a decrease in epididymis lumen size, an irregular shape of the epididymal lumen and an increase in the connective tissue in the interstitium observed in dogs in the 80- and 40-mg/kg dose groups.
- Prostate: When compared with the control group, a reduction in the numbers and size, a thinner epithelium, narrower glandular cavity and increase in the connective tissue in the interstitium were observed in the prostatic acini of dogs in the 80- and 40-mg/kg dose groups.
3.1.8. Toxicokinetics
3.2. Subchronic Toxicology Study on Rats
3.2.1. Clinical Observation
3.2.2. Hematology
3.2.3. Clinical Chemistry
3.2.4. Urinalysis
3.2.5. Bone Marrow Examination
3.2.6. Necropsy
Gross Pathology and Organ Weights
Histopathological Findings
3.2.7. Toxicokinetics
4. Discussion
5. Conclusions
Acknowledgments
Author Contributions
Conflicts of Interest
References
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Animal Number | Frequencies of Vomiting (Days) | Frequencies of Diarrhea (Days) | Animal Number | Frequencies of Vomiting (Days) | Frequencies of Diarrhea (Days) |
---|---|---|---|---|---|
Control | |||||
♂9 | 0 | 0 | ♀14 | 0 | 0 |
♂21 | 0 | 0 | ♀26 | 0 | 0 |
♂29 | 0 | 0 | ♀30 | 0 | 0 |
♂33 | 0 | 0 | ♀36 | 0 | 0 |
5 mg/kg | |||||
♂7 | 0 | 0 | ♀4 | 0 | 0 |
♂31 | 0 | 0 | ♀34 | 0 | 0 |
♂25 | 0 | 0 | ♀38 | 0 | 0 |
♂35 | 0 | 0 | ♀42 | 0 | 0 |
20 mg/kg | |||||
♂15 | 2 | 0 | ♀12 | 1 | 0 |
♂19 | 0 | 0 | ♀16 | 6 | 0 |
♂27 | 2 | 0 | ♀22 | 1 | 0 |
♂37 | 1 | 0 | ♀32 | 4 | 0 |
40 mg/kg | |||||
♂1 | 6 | 1 | ♀10 | 1 | 2 |
♂11 | 9 | 8 | ♀20 | 6 | 0 |
♂23 | 9 | 1 | ♀24 | 3 | 2 |
♂39 | 5 | 3 | ♀28 | 4 | 3 |
80 mg/kg | |||||
♂3 | 9 | 3 | ♀2 | 5 | 8 |
♂5 | 2 | 11 | ♀6 | 4 | 0 |
♂13 | 12 | 5 | ♀8 | 3 | 2 |
♂17 | 4 | 2 | ♀18 | 6 | 9 |
Items | Days | Control | 5 mg/kg | 20 mg/kg | 40 mg/kg | 80 mg/kg | ♀6 a | ♀28 b |
---|---|---|---|---|---|---|---|---|
RBC (×1012/L) | d0 | 6.29 ± 0.68 | 6.31 ± 0.45 | 6.20 ± 0.58 | 6.01 ± 0.31 | 5.92 ± 0.42 | ||
d14 | 6.51 ± 0.76 | 6.23 ± 0.46 | 5.57 ± 0.30 ##,* | 5.6 ± 0.36 ##,* | 5.09 ± 0.42 ##,* | |||
d28 | 6.50 ± 0.54 | 6.22 ± 0.43 | 5.57 ± 0.16 ##,* | 5.00 ± 0.47 ##,* | 4.17 ± 0.33 ##,** | |||
d42 | 6.27 ± 0.36 | 6.21 ± 0.36 | 5.96 ± 0.13 | 5.96 ± 0.06 | 5.71 ± 0.50 | |||
HCT (%) | d0 | 42.4 ± 4.4 | 43.0 ± 2.6 | 42.2 ± 3.9 | 41.7 ± 2.0 | 40.3 ± 3.0 | ||
d14 | 43.2 ± 4.3 | 41.8 ± 2.7 | 36.9 ± 2.2 ##,* | 35.5 ± 2.6 ##,** | 33.4 ± 2.6 ##,* | |||
d28 | 42.7 ± 3.0 | 41.6 ± 2.4 | 36.6 ± 1.0 ##,** | 32.8 ± 2.8 ##,** | 26.9 ± 1.7 ##,** | |||
d42 | 41.8 ± 2.3 | 41.0 ± 1.8 | 39.4 ± 1.7 | 39.7 ± 0.1 | 37.5 ± 3.1 | |||
HGB (g/L) | d0 | 142 ± 14 | 139 ± 8 | 142 ± 13 | 139 ± 6 | 134 ± 10 | ||
d14 | 139 ± 14 | 138 ± 9 | 118 ± 7 ##,** | 114 ± 8 ##,** | 107 ± 8 ##,** | |||
d28 | 137 ± 9 | 135 ± 8 | 118 ± 3 ##,** | 105 ± 9 ##,** | 86 ± 5 ##,** | |||
d42 | 136 ± 7 | 134 ± 7 | 128 ± 8 | 124 ± 1 | 126 ± 4 | |||
RET (%) | d0 | 0.87 ± 0.34 | 0.77 ± 0.38 | 0.96 ± 0.24 | 0.86 ± 0.17 | 0.92 ± 0.27 | 1.37 | 0.75 |
d14 | 0.63 ± 0.29 | 0.62 ± 0.29 | 0.53 ± 0.23 * | 0.13 ± 0.11 ##,** | 0.08 ± 0.12 ##,** | 0.14 | 0.04 | |
d28 | 0.48 ± 0.21 | 0.49 ± 0.23 | 0.54 ± 0.19 ** | 0.51 ± 0.22* | 0.21 ± 0.16 #,** | |||
d42 | 0.65 ± 0.25 | 0.61 ± 0.22 | 0.83 ± 0.23 | 0.89 ± 0.65 | 0.88 ± 0.27 | |||
MON (%) | d0 | 4.8 ± 1.0 | 4.4 ± 1.6 | 4.7 ± 1.3 | 6.0 ± 1.8 | 5.0 ± 0.8 | ||
d14 | 4.5 ± 1.3 | 4.2 ± 1.0 | 8.0 ± 2.3 ** | 9.2 ± 5.3 | 19.7 ± 19.7 # | |||
d28 | 4.7 ± 1.0 | 4.4 ± 1.4 | 9.0 ± 1.4 #,** | 11.6 ± 4.5 ## | 12.5 ± 2.9 ##,** | |||
d42 | 4.7 ± 1.0 | 4.0 ± 1.2 | 5.8 ± 1.0 | 6.4 ± 3.5 | 5.0 ± 1.9 | |||
APTT (s) | d0 | 12.7 ± 0.8 | 13.6 ± 0.6 | 12.4 ± 0.3 | 12.8 ± 0.5 | 13.4 ± 0.6 | 13.9 | 12.4 |
d14 | 13.0 ± 0.9 | 13.2 ± 0.6 | 12.5 ± 0.5 | 16.8 ± 0.7 ##,** | 16.2 ± 3.0 ## | 48.7 | 18.5 | |
d28 | 12.1 ± 0.9 | 13.1 ± 0.5 | 12.0 ± 0.7 | 12.8 ± 0.8 | 12.5 ± 0.5 ** | |||
d42 | 13.8 ± 1.0 | 13.4 ± 0.4 | 12.8 ± 0.3 | 12.9 ± 0.8 | 12.7 ± 0.9 | |||
FIB (g/L) | d0 | 3.86 ± 0.86 | 2.25 ± 0.37 | 4.07 ± 0.94 | 4.84 ± 0.89 | 3.80 ± 0.84 | ||
d14 | 3.93 ± 1.26 | 2.53 ± 0.46 | 4.30 ± 1.17 | 7.19 ± 1.58 ## | 7.06 ± 2.14 ##,** | |||
d28 | 3.18 ± 0.58 | 2.56 ± 0.40 | 4.48 ± 1.68 | 4.93 ± 1.22 | 6.69 ± 0.62 ##,** | |||
d42 | 2.96 ± 0.70 | 2.89 ± 0.60 | 4.26 ± 0.49 | 4.22 ± 1.25 | 3.72 ± 2.00 |
Items | Days | Control | 5 mg/kg | 20 mg/kg | 40 mg/kg | 80 mg/kg | ♀6 a | ♀28 b |
---|---|---|---|---|---|---|---|---|
ALT (nmol/s/L) | d0 | 590 ± 167 | 559 ± 120 | 535 ± 92 | 526 ± 179 | 591 ± 143 | 487 | 428 |
d14 | 563 ± 196 | 521 ± 116 | 425 ± 105 ** | 433 ± 304 | 312 ± 38 * | 466 | 852 | |
d28 | 611 ± 155 | 593 ± 105 | 486 ± 90 | 347 ± 78 * | 307 ± 51 ** | |||
d42 | 562 ± 165 | 558 ± 90 | 523 ± 148 | 514 ± 112 | 549 ± 181 | |||
AST (nmol/s/L) | d0 | 436 ± 85 | 463 ± 106 | 456 ± 92 | 462 ± 57 | 493 ± 103 | 456 | 398 |
d14 | 472 ± 72 | 442 ± 105 | 384 ± 56 * | 313 ± 23 ** | 386 ± 104 | 1907 | 4924 | |
d28 | 419 ± 68 | 424 ± 109 | 408 ± 57 | 378 ± 71 * | 310 ± 59 ** | |||
d42 | 470 ± 68 | 451 ± 79 | 412 ± 31 | 468 ± 80 | 460 ± 83 | |||
LDH (μmol/s/L) | d0 | 3.02 ± 1.38 | 3.08 ± 1.36 | 2.85 ± 0.86 | 3.39 ± 1.55 | 2.71 ± 0.97 | 2.78 | 2.21 |
d14 | 2.28 ± 0.37 | 2.27 ± 1.24 | 1.23 ± 0.45 ** | 1.29 ± 0.68 | 1.76 ± 1.85 | 2.91 | 2.06 | |
d28 | 2.59 ± 0.45 | 2.71 ± 1.12 | 1.54 ± 0.74 * | 2.76 ± 2.49 | 0.97 ± 0.30 ** | |||
d42 | 2.25 ± 0.27 | 2.21 ± 1.32 | 2.28 ± 0.93 | 3.50 ± 2.49 | 3.20 ± 1.62 ** | |||
CPK (μmol/s/L) | d0 | 2.98 ± 0.63 | 2.94 ± 1.40 | 2.98 ± 0.64 | 3.27 ± 0.76 | 3.24 ± 0.77 | 3.06 | 2.47 |
d14 | 2.78 ± 0.27 | 2.63 ± 1.36 | 2.43 ± 0.48 | 2.36 ± 0.19 * | 3.29 ± 1.86 | 57.57 | 6.39 | |
d28 | 2.58 ± 0.29 | 2.43 ± 0.19 | 2.38 ± 0.53 ** | 3.00 ± 0.94 | 1.73 ± 0.24 ** | |||
d42 | 2.56 ± 0.20 | 2.97 ± 0.18 | 2.17 ± 0.30 | 3.00 ± 1.32 | 2.86 ± 0.53 | |||
ALP (μmol/s/L) | d0 | 1.55 ± 0.43 | 1.47 ± 0.30 | 1.48 ± 0.48 | 1.62 ± 0.40 | 1.62 ± 0.49 | 1.50 | 1.33 |
d14 | 1.49 ± 0.28 | 1.45 ± 0.35 | 0.85 ± 0.25 ** | 1.03 ± 0.32 ** | 1.27 ± 1.15 | 3.86 | 3.16 | |
d28 | 1.52 ± 0.48 | 1.51 ± 0.29 | 0.98 ± 0.27 ** | 1.30 ± 0.24 | 1.01 ± 0.27 ** | |||
d42 | 1.27 ± 0.20 | 1.45 ± 0.37 | 1.00 ± 0.24 | 1.34 ± 0.34 | 0.99 ± 0.14 | |||
TBIL (μmol/L) | d0 | 2.50 ± 0.30 | 2.34 ± 0.31 | 2.55 ± 0.28 | 2.24 ± 0.24 | 2.64 ± 0.41 | 2.95 | 2.18 |
d14 | 2.17 ± 0.46 | 2.01 ± 0.41 | 1.85 ± 0.16 | 1.81 ± 0.24 | 2.74 ± 2.93 | 11.53 | 9.65 | |
d28 | 2.17 ± 0.36 | 2.08 ± 0.52 | 2.29 ± 0.31 | 2.04 ± 0.43 | 2.19 ± 0.20 | |||
d42 | 1.99 ± 0.39 | 2.01 ± 0.33 | 1.88 ± 0.19 | 1.88 ± 0.08 | 1.90 ± 0.23 | |||
BU (mmol/L) | d0 | 4.29 ± 1.07 | 4.03 ± 0.52 | 4.35 ± 0.98 | 3.95 ± 0.48 | 4.38 ± 0.72 | 4.04 | 4.08 |
d14 | 4.00 ± 0.75 | 4.10 ± 0.90 | 4.52 ± 1.05 | 4.52 ± 1.05 | 4.66 ± 0.93 | 15.20 | 4.89 | |
d28 | 3.63 ± 0.31 | 3.82 ± 0.51 | 5.37 ± 1.78 | 4.66 ± 0.96 | 5.25 ± 1.21 | |||
d42 | 4.74 ± 0.40 | 4.83 ± 0.20 | 4.05 ± 0.37 | 4.87 ± 1.56 | 4.93 ± 0.50 | |||
TCH (mmol/L) | d0 | 4.45 ± 0.70 | 4.28 ± 0.36 | 4.31 ± 0.36 | 5.38 ± 1.95 | 4.03 ± 1.04 | 3.27 | 5.85 |
d14 | 4.08 ± 0.78 | 3.98 ± 0.64 | 3.16 ± 0.34 | 4.47 ± 0.71 | 4.62 ± 2.51 | 11.04 | 10.73 | |
d28 | 4.48 ± 0.80 | 4.24 ± 0.56 | 3.95 ± 0.55 | 4.66 ± 1.85 | 4.16 ± 1.39 | |||
d42 | 4.12 ± 1.21 | 3.99 ± 0.41 | 3.81 ± 0.18 | 4.55 ± 1.10 | 3.52 ± 0.84 | 0.31 | 0.39 | |
TG (mmol/L) | d0 | 0.43 ± 0.12 | 0.43 ± 0.11 | 0.42 ± 0.09 | 0.41 ± 0.10 | 0.38 ± 0.15 | 1.60 | 1.40 |
d14 | 0.38 ± 0.15 | 0.39 ± 0.08 | 0.29 ± 0.08 | 0.41 ± 0.12 | 0.56 ± 0.28 | |||
d28 | 0.33 ± 0.08 | 0.35 ± 0.11 | 0.34 ± 0.05 | 0.43 ± 0.18 | 0.45 ± 0.11 | |||
d42 | 0.29 ± 0.05 | 0.31 ± 0.09 | 0.33 ± 0.12 | 0.45 ± 0.04 | 0.40 ± 0.14 | |||
CREA (μmol/L) | d0 | 50.9 ± 7.9 | 51.5 ± 9.3 | 51.6 ± 7.5 | 49.2 ± 6.2 | 53.4 ± 5.2 | 52.8 | 47.9 |
d14 | 50.3 ± 5.5 | 51.0 ± 9.9 | 58.6 ± 10.6 | 52.5 ± 6.1 | 58.2 ± 4.8 | 82.4 | 37.8 | |
d28 | 50.9 ± 5.2 | 51.4 ± 10.9 | 52.1 ± 10.3 | 52.6 ± 9.8 | 54.3 ± 8.9 | |||
d42 | 56.4 ± 5.7 | 55.6 ± 4.5 | 49.6 ± 0.6 | 58.8 ± 2.0 | 65.9 ± 11.3 |
Organ | Days | Control | 5 mg/kg | 20 mg/kg | 40 mg/kg | 80 mg/kg | ♂23 | ♂5 |
---|---|---|---|---|---|---|---|---|
Absolute weight | ||||||||
Lung (g) | d28 | 69.9 ± 3.0 | 72.7 ± 8.2 | 71.4 ± 12.6 | 92.4 ± 15.4 | 95.8 ± 35.3 | 109.8 | 135.9 |
d42 | 74.7 ± 7.1 | ± | 74.0 ± 8.8 | 70.4 ± 5.0 | 82.9 ± 6.8 | |||
Testis (g) | d28 | 13.625 ± 0.714 | 13.550 ± 0.494 | 13.953 ± 0.081 | 6.631 ± 2.855 ** | 5.660 ± 1.608 ** | ||
d42 | 12.820 ± 1.556 | 14.050 ± 0.212 | 12.179 ± 0.518 | 9.400 ± 0.063 ** | 6.017 ± 2.937 ** | |||
Relative weight | ||||||||
Lung | d28 | 6.93 ± 0.52 | 6.90 ± 0.90 | 6.96 ± 1.02 | 9.87 ± 2.14 | 9.87 ± 3.27 | 12.34 | 13.39 |
d42 | 7.46 ± 0.43 | ± | 7.37 ± 0.67 | 7.10 ± 1.13 | 8.49 ± 0.95 | |||
Testis | d28 | 1.44 ± 0.02 | 1.23 ± 0.03 | 1.31 ± 0.26 | 0.69 ± 0.24 ** | 0.61 ± 0.23 ** | ||
d42 | 1.29 ± 0.08 | 1.45 ± 0.04 | 1.21 ± 0.01 | 0.78 ± 0.21 ** | 0.63 ± 0.31 ** |
Organ | Findings | Dose (mg/kg/day) | ||||
---|---|---|---|---|---|---|
0 | 5 | 20 | 40 | 80 | ||
Lung | large confluent bronchopneumonia | 0/4 | 0/4 | 0/4 | 2/4 | 2/4 |
Bone marrow of sternum | decrease in hematopoietic cell numbers | 0/4 | 0/4 | 0/4 | 2/4 | 3/4 |
Testis | Reduction in numbers and types of spermatogenic cells | 0/2 | 0/2 | 0/2 | 2/2 | 2/2 |
Epididymis | lack of mature sperm and secretions in the epididymal lumen as well as decrease of epididymal lumen size | 0/2 | 0/2 | 0/2 | 2/2 | 2/2 |
Prostate | reduction in numbers and size, thinner epithelium, narrowing of the glandular cavity of prostatic acini | 0/2 | 0/2 | 0/2 | 2/2 | 2/2 |
Dose (mg/kg/day) | Duration of Administration | AUC0–∞ (ng·h·mL−1) | Cmax (ng·mL−1) | Tmax (h) | t1/2 (h) |
---|---|---|---|---|---|
5 (n = 6) | single | 193.1 ± 64.6 | 35.6 ± 15.1 | 3.67 ± 1.52 | 4.40 ± 0.61 |
14 days | 198.9 ± 69.6 | 30.1 ± 14.2 | 4.20 ± 2.01 | 4.75 ± 1.23 | |
28 days | 616.1 ± 242.4 | 65.7 ± 42.0 | 4.33 ± 2.94 | 7.34 ± 1.02 | |
20 (n = 6) | single | 1191.2 ± 319.9 | 139.1 ± 73.4 | 3.50 ± 2.51 | 5.54 ± 1.53 |
14 days | 620.3 ± 248.7 | 68.1 ± 22.8 | 4.00 ± 2.19 | 5.21 ± 0.53 | |
28 days | 388.9 ± 103.8 | 55.2 ± 21.8 | 3.17 ± 1.33 | 5.35 ± 0.73 | |
40 (n = 6) | single | 2500.4 ± 1490.8 | 456.0 ± 375.5 | 2.70 ± 2.70 | 6.93 ± 3.03 |
14 days | 1021.5 ± 976.6 | 199.0 ± 174.6 | 1.90 ± 1.34 | 7.34 ± 3.82 | |
28 days | 927.9 ± 297.5 | 162.2 ± 101.6 | 2.20 ± 1.10 | 5.08 ± 1.04 | |
80 (n = 6) | single | 3874.9 ± 2632.8 | 365.4 ± 256.7 | 3.50 ± 2.51 | 6.74 ± 2.20 |
14 days | 1547.4 ± 758.0 | 173.5 ± 123.0 | 4.43 ± 3.53 | 7.23 ± 3.45 | |
28 days | 1820.9 ± 570.0 | 180.2 ± 83.4 | 4.60 ± 3.29 | 7.56 ± 3.27 |
Items | Days | Control | 20 mg/kg | 60 mg/kg | 120 mg/kg |
---|---|---|---|---|---|
Female | |||||
WBC | d28 | 3.32 ± 0.54 | 3.17 ± 1.23 | 2.82 ± 0.60 | 3.95 ± 0.77 |
(×109·L−1) | d42 | 3.78 ± 0.92 | 2.68 ± 0.63 * | 2.53 ± 0.60 * | 3.00 ± 0.43 |
FIB | d28 | 1.78 ± 0.11 | 1.87 ± 0.09 | 1.89 ± 0.06 | 2.01 ± 0.40 |
(g/L) | d42 | 1.89 ± 0.19 | 1.62 ± 0.17 * | 1.62 ± 0.18 * | 1.85 ± 0.12 |
APTT | d28 | 24.3 ± 1.7 | 24.3 ± 3.5 | 23.0 ± 2.4 | 22.6 ± 2.4 |
(s) | d42 | 26.2 ± 2.0 | 22.2 ± 3.0 ** | 25.2 ± 1.3 | 25.2 ± 1.6 |
Neu | d28 | 8.40 ± 0.80 | 8.70 ± 1.72 | 12.08 ± 4.77 | 19.28 ± 8.26 |
(%) | d42 | 12.42 ± 1.73 | 11.58 ± 4.04 | 12.06 ± 6.70 | 10.76 ± 1.81 |
Lym | d28 | 88.40 ± 0.77 | 88.38 ± 1.68 | 84.70 ± 5.45 | 77.22 ± 8.78 |
(%) | d42 | 84.30 ± 1.57 | 85.40 ± 3.85 | 85.36 ± 6.93 | 85.88 ± 1.85 |
Males | |||||
RET | d28 | 1.61 ± 0.21 | 1.88 ± 0.32 | 1.43 ± 0.22 | 2.04 ± 0.31 * |
(%) | d42 | 2.03 ± 1.19 | 1.92 ± 0.31 | 1.82 ± 0.43 | 2.16 ± 0.22 |
Organ | Days | Control | 20 mg/kg | 60 mg/kg | 120 mg/kg |
---|---|---|---|---|---|
Absolute weight (female) | |||||
Adrenal gland (g) | d28 | 0.068 ± 0.007 | 0.081 ± 0.005 ** | 0.068 ± 0.003 | 0.066 ± 0.008 |
d42 | 0.077 ± 0.009 | 0.072 ± 0.008 | 0.071 ± 0.012 | 0.069 ± 0.011 | |
Relative weight (female) | |||||
Brain (g/100 g) | d28 | 0.799 ± 0.045 | 0.728 ± 0.047 * | 0.799 ± 0.062 | 0.834 ± 0.042 |
d42 | 0.739 ± 0.045 | 0.768 ± 0.020 | 0.768 ± 0.068 | 0.745 ± 0.089 | |
Absolute weight (male) | |||||
Testis (g) | d28 | 2.774 ± 0.209 | 2.707 ± 0.090 | 2.624 ± 0.170 | 2.666 ± 0.115 |
d42 | 2.546 ± 0.082 | 2.798 ± 0.112 ** | 2.787 ± 0.097 ** | 2.723 ± 0.161 * | |
Relative weight (male) | |||||
Kidney (g/100 g) | d28 | 0.759 ± 0.051 | 0.707 ± 0.024 * | 0.705 ± 0.039 * | 0.673 ± 0.023 ** |
d42 | 0.705 ± 0.028 | 0.693 ± 0.033 | 0.687 ± 0.020 | 0.624 ± 0.053 ** |
Dose (mg/kg/day) | Duration of Administration | AUC0–∞ (ng·h·mL−1) | Cmax (ng·mL−1) | Tmax (h) | t1/2 (h) |
---|---|---|---|---|---|
20 (n = 6) | single | 8.0 ± 9.1 | 7.5 ± 7.2 | 0.86 ± 1.54 | 0.60 ± 0.37 |
28 days | 32.7 ± 14.9 | 12.9 ± 9.5 | 0.34 ± 0.18 | 7.32 ± 2.93 | |
60 (n = 6) | single | 39.1 ± 15.0 | 13.3 ± 5.5 | 0.50 ± 0.00 | 6.83 ± 2.69 |
28 days | 114.1 ± 30.9 | 19.7 ± 3.3 | 0.28 ± 0.17 | 7.57 ± 2.31 | |
120 (n = 6) | single | 69.9 ± 22.9 | 20.4 ± 3.8 | 0.45 ± 0.13 | 6.51 ± 1.62 |
28 days | 446.8 ± 282.2 | 57.5 ± 26.1 | 1.92 ± 3.07 | 7.03 ± 1.90 |
© 2016 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC-BY) license (http://creativecommons.org/licenses/by/4.0/).
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Zhang, X.; Zhang, X.; Yuan, B.; Ren, L.; Zhang, T.; Lu, G. Subchronic Toxicities of HZ1006, a Hydroxamate-Based Histone Deacetylase Inhibitor, in Beagle Dogs and Sprague-Dawley Rats. Int. J. Environ. Res. Public Health 2016, 13, 1190. https://doi.org/10.3390/ijerph13121190
Zhang X, Zhang X, Yuan B, Ren L, Zhang T, Lu G. Subchronic Toxicities of HZ1006, a Hydroxamate-Based Histone Deacetylase Inhibitor, in Beagle Dogs and Sprague-Dawley Rats. International Journal of Environmental Research and Public Health. 2016; 13(12):1190. https://doi.org/10.3390/ijerph13121190
Chicago/Turabian StyleZhang, Xiaofang, Xiaodong Zhang, Bojun Yuan, Lijun Ren, Tianbao Zhang, and Guocai Lu. 2016. "Subchronic Toxicities of HZ1006, a Hydroxamate-Based Histone Deacetylase Inhibitor, in Beagle Dogs and Sprague-Dawley Rats" International Journal of Environmental Research and Public Health 13, no. 12: 1190. https://doi.org/10.3390/ijerph13121190