Synthesis, Biological Evaluation, and Pharmacokinetic Study of Novel Liguzinediol Prodrugs
Abstract
:1. Introduction
2. Results and Discussion
2.1. Chemistry
2.2. Metabolic Stability
2.3. Formation of Parent Compound from Prodrugs in Rat Liver Microsomes and Rat Plasma
2.4. Cardiac Function Screening
2.5. Application to a Pharmacokinetic Study
Compd | Group | LVDP | ∆% | +dP/dtmax | ∆% | −dP/dtmax | ∆% | HR |
---|---|---|---|---|---|---|---|---|
(μM) | (mmHg) | (mmHg/s) | (mmHg/s) | (beat·min−1) | ||||
1a | 0 | 50 ± 2.8 | 1,685 ± 147 | −1,058 ± 81 | 183 ± 22 | |||
1 | 60 ± 5 b | 19.4 ± 11.0 | 1,836 ± 121 | 9.4 ± 8.1 | −1,175 ± 125 | 11.1 ± 10.0 | 186 ± 29 | |
10 | 73 ± 4 bd | 45.6 ± 9.0 | 2,125 ± 242 bc | 26.5 ± 13.4 | −1,371 ± 186 bc | 30.3 ± 0.3 | 209 ± 21 | |
100 | 88 ± 3 bdf | 76.3 ± 12.3 | 2,702 ± 287 bdf | 60.9 ± 17.3 | −1,911 ± 200 bdf | 82.0 ± 27.9 | 193 ± 15 | |
3 | 0 | 55 ± 2.8 | 1,611 ± 27 | −1,086 ± 38 | 207 ± 8 | |||
1 | 63 ± 2 b | 15.0 ± 5.5 | 1,641 ± 29 | 1.9 ± 0.5 | −1,139 ± 76 | 4.9 ± 5.9 | 203 ± 15 | |
10 | 69 ± 1.1 bd | 26.3 ± 7.7 | 1,768 ± 91 bd | 9.8 ± 7.0 | −1,184 ± 75 a | 9.0 ± 5.1 | 204 ± 14 | |
100 | 79 ± 1.6 bdf | 44.7 ± 6.6 | 2,123 ± 82 bdf | 31.8 ± 5.3 | −1,313 ± 70 bdf | 20.9 ± 5.1 | 205 ± 26 | |
4 | control | 54 ± 5 | 1,634 ± 100 | −1,044 ± 84 | 196 ± 21 | |||
1 | 63 ± 3 b | 17.4 ± 9.8 | 1,669 ± 103 | 2.2 ± 3.4 | −1,101 ± 102 | 5.6 ± 8.3 | 213 ± 46 | |
10 | 60 ± 4 a | 14.2 ± 10.0 | 1,765 ± 52 a | 4.9 ± 5.4 | −1,196 ± 54 bc | 9.9 ± 9.5 | 196 ± 16 | |
100 | 73 ± 2.3 bdf | 20.2 ± 15.2 | 1,952 ± 49 bdf | 9.0 ± 8.9 | −1,399 ± 61 bdf | 16.7± 15.2 | 191 ± 29 | |
5 | control | 52 ± 4 | 1,671 ± 93 | −1,081 ± 40 | 209 ± 47 | |||
1 | 55 ± 5 | 5.3 ± 3.3 | 1,688 ± 95 | 1.0 ± 1.1 | −1,095 ± 45 | 1.3 ± 0.8 | 189 ± 30 | |
10 | 59 ± 2.5 b | 13.9 ± 7.4 | 1,831 ± 14 bd | 9.9 ± 5.9 | −1,245 ± 48 bd | 15.3 ± 2.8 | 196 ± 40 | |
100 | 64 ± 2.4 bde | 24.5 ± 11.2 | 1,962 ± 70 bdf | 17.6 ± 6.8 | −1,314 ± 63 bde | 21.7 ± 7.2 | 213 ± 41 |
Dose | 10 mg/kg | 20 mg/kg | 40 mg/kg |
---|---|---|---|
Tmax (h) | 0.42 ± 0.30 | 0.42 ± 0.13 | 0.42 ± 0.13 |
Cmax (mg/L) | 6.50 ± 1.71 | 10.49 ± 3.14 | 28.39 ± 9.56 |
t1/2 (h) | 4.01 ± 1.36 | 4.24 ± 1.52 | 4.39 ± 1.64 |
CL/F (L/h·kg) | 0.40 ± 0.06 | 0.52 ± 0.08 | 0.41 ± 0.06 |
AUC0–t (mg·h/L) | 21.51 ± 2.82 | 33.90 ± 5.71 | 93.94 ± 13.76 |
AUC0–∞ (mg·h/L) | 25.56 ± 3.82 | 38.86 ± 5.72 | 98.30 ± 15.37 |
Dose | 10 mg·kg−1 i.g. | 20 mg·kg−1 i.g. | 50 mg·kg−1 i.g. |
---|---|---|---|
Tmax (h) | 0.29 ± 0.10 | 0.29 ± 0.10 | 0.29 ± 0.10 |
Cmax (mg/L) | 8.58 ± 2.66 | 17.02 ± 5.50 | 49.33 ± 10.50 |
t1/2 (h) | 2.21 ± 1.11 | 2.57 ± 2.14 | 1.78 ± 0.57 |
CL/F (L/h·kg) | 0.79 ± 0.51 | 0.86 ± 0.57 | 0.98 ± 1.01 |
AUC0–t (mg·h/L) | 16.74 ± 8.90 | 34.84 ± 24.64 | 92.85 ± 64.10 |
AUC0–∞ (mg·h/L) | 17.08 ± 8.99 | 35.93 ± 24.08 | 94.82 ± 66.88 |
3. Experimental
3.1. General
3.2. Chemistry
3.3. Metabolic Stability Analysis
3.3.1. Rat Plasma
In Vitro Physiological Stability of Prodrugs 3–5 and LZDO (1a) in Rat Plasma
3.3.2. Rat Liver Microsomes
3.3.2.1. Materials
3.3.2.2. Assay Procedure
3.4. Ex Vivo Langendorff-Perfused Rat Heart [25]
3.5. Application to a Pharmacokinetic Study in Rats
4. Conclusions
Supplementary Materials
Acknowledgments
References
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Liu, Z.; Li, W.; Wen, H.-M.; Bian, H.-M.; Zhang, J.; Chen, L.; Chen, L.; Yang, K.-D. Synthesis, Biological Evaluation, and Pharmacokinetic Study of Novel Liguzinediol Prodrugs. Molecules 2013, 18, 4561-4572. https://doi.org/10.3390/molecules18044561
Liu Z, Li W, Wen H-M, Bian H-M, Zhang J, Chen L, Chen L, Yang K-D. Synthesis, Biological Evaluation, and Pharmacokinetic Study of Novel Liguzinediol Prodrugs. Molecules. 2013; 18(4):4561-4572. https://doi.org/10.3390/molecules18044561
Chicago/Turabian StyleLiu, Zheng, Wei Li, Hong-Mei Wen, Hui-Min Bian, Jing Zhang, Lei Chen, Long Chen, and Kun-Di Yang. 2013. "Synthesis, Biological Evaluation, and Pharmacokinetic Study of Novel Liguzinediol Prodrugs" Molecules 18, no. 4: 4561-4572. https://doi.org/10.3390/molecules18044561