Effect of Sipjeondaebo-Tang on the Pharmacokinetics of S-1, an Anticancer Agent, in Rats Evaluated by Population Pharmacokinetic Modeling
Abstract
:1. Introduction
2. Results
2.1. Pharmacokinetics of S-1 after Pretreatment with a Single Dose of SDT
2.2. Pharmacokinetics of S-1 after Pretreatment with Multiple Doses of SDT
2.3. Population Pharmacokinetic (POP-PK) Modeling
3. Discussion
4. Materials and Methods
4.1. Materials
4.2. Animal Study
4.3. LC/MS/MS
4.4. Noncompartmental Analysis
4.5. Population Pharmacokinetic Modeling
4.6. Statistical Analysis
Acknowledgments
Author Contributions
Conflicts of Interest
References
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Sample Availability: Samples of the compounds are not available from the authors. |
Parameter | Single Dose | Multiple Dose | |||
---|---|---|---|---|---|
Control (n = 5) | SDT (n = 5) | Control (n = 5) | SDT (n = 5) | ||
Tegafur | t1/2 (h) | 2.3 ± 0.7 | 3.5 ± 0.7 * | 2.2 ± 1.4 | 3.3 ± 0.8 |
Tmax (h) | 1.5 ± 0.4 | 1.3 ± 0.4 | 1.2 ± 0.7 | 3.2 ± 1.6 * | |
Cmax (ng/mL) | 9328.0 ± 3099.3 | 7202.0 ± 2374.7 | 6828.0 ± 384.0 | 4960.0 ± 431.9 * | |
AUCall (ng·h/mL) | 55,372.7 ± 20215.9 | 42,705.1 ± 11087.4 | 43,496.9 ± 4673.0 | 46,842.4 ± 8127.5 | |
AUCinf (ng·h/mL) | 55,712.7 ± 20247.5 | 42,945.5 ± 11033.1 | 43,748.1 ± 4835.6 | 47,461.3 ± 8163.9 | |
CL/F (mL/min/kg) | 1.7 ± 0.8 | 2.1 ± 0.6 | 1.9 ± 0.2 | 1.8 ± 0.3 | |
Vz/F (L/kg) | 0.3 ± 0.1 | 0.6 ± 0.2 * | 0.4 ± 0.2 | 0.5 ± 0.1 | |
5-FU | t1/2 (h) | 2.6 ± 2.1 | 2.2 ± 1.0 | 3.0 ± 0.9 | 3.1 ± 0.8 |
Tmax (h) | 1.7 ± 0.8 | 1.7 ± 1.1 | 1.8 ± 0.3 | 2.4 ± 0.5 | |
Cmax (ng/mL) | 178.2 ± 42.0 | 209.5 ± 94.9 | 172.2 ± 40.4 | 64.3 ± 23.0 * | |
AUCall (ng·h/mL) | 613.7 ± 233.4 | 892.4 ± 439.7 | 639.3 ± 190 | 362.7 ± 96.2 * | |
AUCinf (ng·h/mL) | 924.9 ± 537.6 | 955.8 ± 438.9 | 750.2 ± 145.8 | 429.6 ± 83.2 * | |
AUCmeta/AUCparent (%) | 2.5 ± 0.9 | 3.3 ± 1.0 | 2.7 ± 0.7 | 1.5 ± 0.5 * | |
Gimeracil | t1/2 (h) | 1.2 ± 0.2 | 0.9 ± 0.3 | 0.7 ± 0.1 | 0.8 ± 0.2 |
Tmax (h) | 0.6 ± 0.4 | 0.8 ± 0.8 | 0.5 ± 0.0 | 0.7 ± 0.5 | |
Cmax (ng/mL) | 422.2 ± 136.5 | 358 ± 121.4 | 347.8 ± 42.7 | 142.3 ± 41.8 * | |
AUCall (ng·h/mL) | 768.3 ± 312.9 | 678.7 ± 190.9 | 449.5 ± 74.2 | 180.2 ± 41.5 * | |
AUCinf (ng·h/mL) | 984.8 ± 335.4 | 758.7 ± 186.7 | 526.6 ± 85.4 | 247.4 ± 57.4 * | |
CL/F (mL/min/kg) | 26.8 ± 8.8 | 33.7 ± 9.4 | 46.9 ± 7.8 | 101.9 ± 22.6 * | |
Vz/F (L/kg) | 2.9 ± 1.3 | 2.6 ± 1.4 | 2.8 ± 0.4 | 6.8 ± 0.9 * |
Parameter | Symbol | Unit | Population Mean (BSV) |
---|---|---|---|
Absorption rate constant for tegafur in control group | Ka,Con | 1/h | 0.296 (0.0101) |
Absorption rate constant for tegafur in SDT pretreatment group | Ka,Pretre | 1/h | 0.197 (0.0125) |
Formation rate constant of 5-FU precursor from gut compartment in control group | Ka,Met,Con | 1/h | 0.122 (0.308) |
Formation rate constant of 5-FU precursor from gut compartment in SDT pretreatment group | Ka,Met,Pretre | 1/h | 0.0595 (0.655) |
Formation rate constant of 5-FU from 5-FU precursor | KConv | 1/h | 2.88 (0.747) |
Clearance for tegafur | CLTeg/F | L/h/kg | 0.0813 (0.00221) |
Fraction of 5-FU clearance for 5-FU precursor formation | FMet | - | 0.342 (0.0162) |
Clearance for 5-FU in control group | CL5FU,Con/F | L/h/kg | 3.52 (0.163) |
Clearance for 5-FU in SDT pretreatment group | CL5FU,Pretre/F | L/h/kg | 5.93 (0.025) |
Distribution clearance for tegafur | CLdTeg/F | L/h/kg | 0.184 (0.105) |
Distribution clearance for 5-FU | CLd5FU/F | L/h/kg | 1.87 (0.168) |
Central volume of distribution for tegafur | V1,Teg/F | L/kg | 0.0464 (0.729) |
Central volume of distribution for 5-FU | V1,5FU/F | L/kg | 0.623 (0.291) |
Peripheral volume of distribution for tegafur | V2,Teg/F | L/kg | 0.137 (0.0141) |
Peripheral volume of distribution for 5-FU | V2,5FU/F | L/kg | 0.294 (0.184) |
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Kim, T.H.; Shin, S.; Shin, J.C.; Bulitta, J.B.; Weon, K.-Y.; Yoo, S.D.; Park, G.-Y.; Jeong, S.W.; Kwon, D.R.; Min, B.S.; et al. Effect of Sipjeondaebo-Tang on the Pharmacokinetics of S-1, an Anticancer Agent, in Rats Evaluated by Population Pharmacokinetic Modeling. Molecules 2017, 22, 1488. https://doi.org/10.3390/molecules22091488
Kim TH, Shin S, Shin JC, Bulitta JB, Weon K-Y, Yoo SD, Park G-Y, Jeong SW, Kwon DR, Min BS, et al. Effect of Sipjeondaebo-Tang on the Pharmacokinetics of S-1, an Anticancer Agent, in Rats Evaluated by Population Pharmacokinetic Modeling. Molecules. 2017; 22(9):1488. https://doi.org/10.3390/molecules22091488
Chicago/Turabian StyleKim, Tae Hwan, Soyoung Shin, Jeong Cheol Shin, Jürgen B. Bulitta, Kwon-Yeon Weon, Sun Dong Yoo, Gi-Young Park, Seok Won Jeong, Dong Rak Kwon, Byung Sun Min, and et al. 2017. "Effect of Sipjeondaebo-Tang on the Pharmacokinetics of S-1, an Anticancer Agent, in Rats Evaluated by Population Pharmacokinetic Modeling" Molecules 22, no. 9: 1488. https://doi.org/10.3390/molecules22091488