LC478, a Novel Di-Substituted Adamantyl Derivative, Enhances the Oral Bioavailability of Docetaxel in Rats
Abstract
:1. Introduction
2. Materials and Methods
2.1. Chemicals
2.2. Cell Culture and Cell Viability Assay
2.3. Effect of LC478 on P-gp Mediated Efflux of Rhodamine-123, a P-gp Substate, in Caco-2 Cells
2.4. Effect of LC478 on P-gp Mediated Efflux of Docetaxel in Caco-2 Cells
2.5. Animals
2.6. Pharmacokinetic Studies of Docetaxel with LC478
2.7. Effects of LC478 on Bi-Directional Transport of Rhodamine-123 or Docetaxel Across Rat Duodenum Using the Ussing Chamber
2.8. Effect of LC478 for Disappearance of Docetaxel in Rat Hepatic and Intestinal Microsomes
2.9. Effect of LC478 on Rat Plasma Protein Binding of Docetaxel with LC478
2.10. Analytical Methods of Docetaxel and LC478
2.11. Statistical Analysis
3. Results
3.1. Effect of LC478 on Cace-2 Cell Viability
3.2. Effect of LC478 on P-gp Mediated Efflux of Rhodamine-123, a P-gp Substate, in Caco-2 Cells
3.3. Effect of LC478 on P-gp Mediated Efflux of Docetaxel in Caco-2 Cells
3.4. Effect of LC478 on Pharmacokinetics of Docetaxel
3.5. Effect of LC478 on Bi-Directional Transport of Rhodamine-123 or Docetaxel across Small Intestine in Rats
3.6. Effect of LC478 for Docetaxel Metabolism in Liver and Small Intestine
3.7. Effect of LC478 on Rat Plasma Protein Binding of Docetaxel Using Equilibrium Dialysis
4. Discussion
0.365 = Funabs + (0.0101 × 0.0229) 30 mg/kg oral LC478
0.200 = Funabs + (0.0176 × 0.0396) 100 mg/kg oral LC478
5. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Compounds | Papp (× 10−6 cm/s) | Efflux Ratio | |
---|---|---|---|
Absorptive (A to B) n = 3 | Secretory (B to A) n = 3 | ||
Control | 0.231 ± 0.0388 | 1.50 ± 0.113 a | 6.49 |
1 μM LC478 | 0.226 ± 0.0429 | 1.03 ± 0.264 a,b | 4.56 |
10 μM LC478 | 0.245 ± 0.0469 | 0.555 ± 0.0564 a,b | 2.27 |
10 μM Verapamil | 0.270 ± 0.0634 | 0.634 ± 0.207 a,b | 2.35 |
Parameter | 0 mg/kg | 30 mg/kg | 100 mg/kg |
---|---|---|---|
Intravenous Study | n = 6 | n = 6 | n = 6 |
Body weight (g) | 302 ± 7.45 | 296 ± 4.49 | 301 ± 18.8 |
AUClast (µg min/mL) | 253 ± 38.1 | 290 ± 46.6 | 268 ± 39.2 |
AUCinf (µg min/mL) | 265 ± 39.0 | 303 ± 46.5 | 275 ± 40.2 |
Terminal half-life (min) | 122 ± 36.6 | 144 ± 37.6 | 151 ± 34.5 |
MRT (min) | 57.9 ± 4.63 | 58.0 ± 11.5 | 67.1 ± 14.6 |
CL (mL/min/kg) | 78.4 ± 13.1 | 67.9 ± 11.7 | 70.4 ± 9.10 |
CLR (mL/min/kg) a | 1.13 ± 0.431 | 1.06 ± 0.235 | 0.678 ± 0.253 |
CLNR (mL/min/kg) | 77.2 ± 12.8 | 66.8 ± 11.4 | 69.7 ± 9.13 |
Vss (L/kg) | 4.57 ± 1.03 | 4.02 ± 1.36 | 4.91 ± 1.44 |
Ae0–24 h (% of dose) b | 1.42 ± 0.418 | 1.56 ± 0.129 | 0.979 ± 0.365 |
GI24 h (% of dose) | 0.881 ± 0.411 | 1.01 ± 0.731 | 1.76 ± 0.958 |
Frel (%) | - | 114 | 104 |
Oral Study | n = 5 | n = 6 | n = 6 |
Body weight (g) | 247 ± 2.74 | 244 ± 6.07 | 253 ± 8.54 |
AUClast (µg min/mL) b | 4.97 ± 1.44 | 6.38 ± 1.60 | 9.67 ± 2.05 |
AUCinf (µg min/mL) b | 5.21 ± 1.27 | 6.94 ± 1.74 | 10.9 ± 3.02 |
Cmax (µg/mL) c | 0.0583 ± 0.0207 | 0.124 ± 0.446 | 0.184 ± 0.459 |
Tmax (min) | 15 (5−60) | 30 (15−30) | 30 (15−30) |
CL/F (mL/min/kg) b | 3039 ± 805 | 3167 ± 1021 | 1803 ± 515 |
Vz/F (L/kg) b | 670 ± 170 | 794 ± 175 | 471 ± 117 |
CLR (mL/min/kg) b | 3.50 ± 1.10 | 3.43 ± 1.15 | 1.79 ± 0.474 |
Ae0–24 h (% of dose) | 0.103 ± 0.0510 | 0.104 ± 0.0362 | 0.0870 ± 0.0383 |
GI24 h (% of dose) b | 41.7 ± 13.3 | 36.5 ± 12.6 | 20.0 ± 7.44 |
Fabs (%) | 58.3 | 63.5 | 80.1 |
F (%) | 1.97 | 2.29 | 3.96 |
Frel (%) | - | 133 | 209 |
Compounds | Papp (× 10−6 cm/s) | Efflux Ratio | |
---|---|---|---|
Absorptive (M to S) | Secretory (S to M) | ||
Rhodamine-123 | n = 3 | n = 3 | |
Control | 0.105 ± 0.0387 | 0.629 ± 0.160 a | 5.99 |
1 µM LC478 | 0.103 ± 0.0472 | 0.577 ± 0.0791 a | 5.60 |
10 µM LC478 | 0.188 ± 0.0177 | 0.288 ± 0.108 b | 1.53 |
10 µM verapamil | 0.191 ± 0.0562 | 0.308 ± 0.113 b | 1.61 |
Docetaxel | n = 3 | n = 3 | |
Control | 0.174 ± 0.0721 | 1.08 ± 0.115 a | 6.21 |
1 µM LC478 | 0.171 ± 0.0639 | 0.943 ± 0.283 a | 5.51 |
10 µM LC478 | 0.262 ± 0.0139 b | 0.574 ± 0.101 a,b | 2.19 |
10 µM verapamil | 0.230 ± 0.0303 b | 0.408 ± 0.0959 a,b | 1.77 |
Parameters | Concentrations of LC478 (µM) | |||
---|---|---|---|---|
0 | 1 | 5 | 10 | |
Hepatic microcomes | n = 3 | n = 3 | n = 3 | n = 3 |
Km (µM) | 20.2 ± 2.78 | 20.6 ± 2.09 | 21.4 ± 2.65 | 23.1 ± 1.74 |
Vmax (nmol/min/mg protein) | 0.464 ± 0.107 | 0.461 ± 0.0474 | 0.438 ± 0.0578 | 0.427 ± 0.0411 |
CLint (µL/min/mg protein) | 0.0229 ± 0.00204 | 0.0226 ± 0.00454 | 0.0206 ± 0.00280 | 0.0187 ± 0.00314 |
Intestinal microsomes | n = 3 | n = 3 | n = 3 | n = 3 |
Km (µM) | 18.1 ± 1.20 | 18.3 ± 7.07 | 20.2 ± 8.94 | 17.4 ± 1.01 |
Vmax (nmol/min/0.3 mg protein) | 0.109 ± 0.0502 | 0.133 ± 0.0343 | 0.133 ± 0.0737 | 0.105 ± 0.0355 |
CLint (µL/min/0.3 mg protein) | 0.00603 ± 0.00291 | 0.00767 ± 0.00158 | 0.00757 ± 0.00559 | 0.00688 ± 0.00349 |
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Han, S.Y.; Lu, Q.; Lee, K.; Choi, Y.H. LC478, a Novel Di-Substituted Adamantyl Derivative, Enhances the Oral Bioavailability of Docetaxel in Rats. Pharmaceutics 2019, 11, 135. https://doi.org/10.3390/pharmaceutics11030135
Han SY, Lu Q, Lee K, Choi YH. LC478, a Novel Di-Substituted Adamantyl Derivative, Enhances the Oral Bioavailability of Docetaxel in Rats. Pharmaceutics. 2019; 11(3):135. https://doi.org/10.3390/pharmaceutics11030135
Chicago/Turabian StyleHan, Seung Yon, Qili Lu, Kyeong Lee, and Young Hee Choi. 2019. "LC478, a Novel Di-Substituted Adamantyl Derivative, Enhances the Oral Bioavailability of Docetaxel in Rats" Pharmaceutics 11, no. 3: 135. https://doi.org/10.3390/pharmaceutics11030135
APA StyleHan, S. Y., Lu, Q., Lee, K., & Choi, Y. H. (2019). LC478, a Novel Di-Substituted Adamantyl Derivative, Enhances the Oral Bioavailability of Docetaxel in Rats. Pharmaceutics, 11(3), 135. https://doi.org/10.3390/pharmaceutics11030135