Alterations in Pharmacokinetics of Gemcitabine and Erlotinib by Concurrent Administration of Hyangsayukgunja-Tang, a Gastroprotective Herbal Medicine
Abstract
:1. Introduction
2. Results
2.1. Pharmacokinetics of Gemcitabine and Its Metabolite dFdU in Rats Pretreated with HYT
2.2. Pharmacokinetics of Erlotinib and Its Metabolites OSI-420 and OSI-413 in Rats Pretreated with HYT
2.3. Pharmacokinetic Modeling
3. Discussion
4. Materials and Methods
4.1. Materials
4.2. Animal Study
4.3. LC-MS/MS
4.4. Non-Compartmental Pharmacokinetic Analysis
4.5. 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 Doses | |||
---|---|---|---|---|---|
Control (n = 7) | HYT (n = 6) | Control (n = 4) | HYT (n = 5) | ||
Gemcitabine | t1/2 (h) | 7.9 ± 1.2 | 9.8 ± 0.8 * | 12.1 ± 2.1 | 10.6 ± 2.4 |
C0 (ng/mL) | 10,067.5 ± 2101.4 | 10,562.9 ± 1241.2 | 10,163.2 ± 1938.0 | 10,098.7 ± 820.5 | |
AUCall (ng·h/mL) | 34,684.2 ± 6088.4 | 30,934.6 ± 4475.8 | 37,842.2 ± 9170.3 | 29,383.8 ± 3473.1 | |
AUCinf (ng·h/mL) | 34,931.4 ± 6017.6 | 31,222.8 ± 4518.1 | 38,585.6 ± 9292.4 | 29,705.9 ± 3561.8 | |
Vz/F (L/kg) | 3.4 ± 0.9 | 4.6 ± 1.0 * | 4.9 ± 2.0 | 5.2 ± 1.4 | |
CL/F (mL/min/kg) | 4.9 ± 1.0 | 5.4 ± 0.8 | 4.5 ± 1.1 | 5.7 ± 0.7 | |
Vss (L/kg) | 1.7 ± 0.3 | 1.9 ± 0.1 | 2.1 ± 0.3 | 1.9 ± 0.1 | |
dFdU | t1/2 (h) | 29.2 ± 7.2 | 41.5 ± 28.6 | 24.4 ± 3.9 | 29.6 ± 5.7 |
Tmax (h) | 6.3 ± 3.1 | 7.3 ± 3.0 | 9.0 ± 2.0 | 5.6 ± 2.2 * | |
Cmax (ng/mL) | 550.7 ± 68.1 | 538.3 ± 93.9 | 885 ± 112.5 | 722 ± 141.8 | |
AUCall (ng·h/mL) | 16,597.2 ± 2484 | 16,228.1 ± 5943.2 | 27,104.5 ± 2154.8 | 20,919.8 ± 7518.3 | |
AUCinf (ng·h/mL) | 22,137.7 ± 5022.7 | 21,221.6 ± 6950.8 | 35,453.2 ± 7118.4 | 25,824.8 ± 9709 | |
AUCmeta/AUCparent | 0.64 ± 0.14 | 0.67 ± 0.18 | 0.74 ± 0.14 | 0.70 ± 0.17 |
Parameter | Single Dose | Multiple Doses | |||
---|---|---|---|---|---|
Control (n = 7) | HYT (n = 6) | Control (n = 4) | HYT (n = 5) | ||
Erlotinib | t1/2 (h) | 5.9 ± 4.0 | 5.3 ± 2.6 | 4.3 ± 1.8 | 6.8 ± 3.5 |
Tmax (h) | 0.8 ± 0.4 | 1.1 ± 0.5 | 1.0 ± 0.0 | 1.5 ± 0.7 | |
Cmax (ng/mL) | 2653.8 ± 760.3 | 3092 ± 1142.4 | 2484.5 ± 797.4 | 2449.3 ± 1390 | |
AUCall (ng·h/mL) | 11,544.5 ± 2210.6 | 13,419.5 ± 2713.9 | 14,218.5 ± 3731.5 | 12,422.6 ± 1026.3 | |
AUCinf (ng·h/mL) | 11,811.6 ± 2211.8 | 13,517 ± 2678.2 | 14,237.8 ± 3737.1 | 12,509.4 ± 1022.4 | |
CL/F (mL/min/kg) | 14.5 ± 9.8 | 12.1 ± 7.1 | 9.1 ± 3.2 | 15.7 ± 7.4 | |
Vz/F (L/kg) | 29.1 ± 5.5 | 25.7 ± 6.5 | 24.7 ± 6.6 | 26.8 ± 2.4 | |
OSI-420 | t1/2 (h) | 6.8 ± 4.5 | 3.9 ± 2.2 | 3.6 ± 0.8 | 5.9 ± 4.0 |
Tmax (h) | 2.0 ± 0.0 | 2.3 ± 0.8 | 4.8 ± 3.8 | 3.7 ± 2.8 | |
Cmax (ng/mL) | 202.3 ± 87.1 | 238.1 ± 88.7 | 167.3 ± 44.7 | 114.7 ± 15.6 * | |
AUCall (ng·h/mL) | 1553.3 ± 386.7 | 1568.5 ± 393.2 | 1666.5 ± 663.4 | 865 ± 223.8 * | |
AUCinf (ng·h/mL) | 1598.6 ± 368.3 | 1617.4 ± 410.2 | 1689.9 ± 662 | 955.6 ± 171.5 | |
AUCmeta/AUCparent | 0.14 ± 0.03 | 0.12 ± 0.02 | 0.12 ± 0.03 | 0.08 ± 0.01 * | |
OSI-413 | t1/2 (hr) | 7.1 ± 5.8 | 5.8 ± 2.7 | 5.6 ± 1.4 | 5.7 ± 0.9 |
Tmax (hr) | 2.9 ± 2.3 | 3.3 ± 2.4 | 4.8 ± 3.8 | 3.7 ± 2.8 | |
Cmax (ng/mL) | 1164.6 ± 493.7 | 1349.3 ± 508.9 | 1039 ± 259.7 | 649.4 ± 115.6 * | |
AUCall (ng·h/mL) | 10,044.5 ± 3162.8 | 10,300.6 ± 3230.6 | 11,199.6 ± 3637.9 | 5671.4 ± 1018.4 * | |
AUCinf (ng·h/mL) | 10,196.9 ± 2995.2 | 10,334.4 ± 3228.5 | 11,219.4 ± 3647.3 | 5697.5 ± 1007.6 * | |
AUCmeta/AUCparent | 0.88 ± 0.28 | 0.83 ± 0.27 | 0.82 ± 0.17 | 0.47 ± 0.07 * |
Parameter | Symbol | Unit | Population Mean (BSV) |
---|---|---|---|
Absorption rate constant for erlotinib | ka | 1/h | 1.14 (0.81) |
Absorption lag time for erlotinib | Tlag | h | 0.155 (0.777) |
Clearance for erlotinib | CLerlotinib/F | L/h/kg | 1.5 (0.148) |
Fraction of erlotinib clearance for metabolite formation | Fmet | - | 0.1 |
Clearance for OSI-420 in control group | CLOSI420,con/F | L/h/kg | 0.182 (0.174) |
Clearance for OSI-420 in HYT pretreatment group | CLOSI420,HYT/F | L/h/kg | 0.35 (0.122) |
Clearance for OSI-413 in control group | CLOSI413,con/F | L/h/kg | 1.18 (0.257) |
Clearance for OSI-413 in HYT pretreatment group | CLOSI413,HYT/F | L/h/kg | 2.22 (0.163) |
Distribution clearance for erlotinib | CLDerlotinib/F | L/h/kg | 2.68 (0.655) |
Distribution clearance for OSI-420 | CLDOSI420/F | L/h/kg | 4.51 (0.0598) |
Distribution clearance for OSI-413 | CLDOSI413/F | L/h/kg | 0.943 (0.0244) |
Central volume of distribution for erlotinib | V1,erlotinib/F | L/kg | 3.97 (0.0473) |
Peripheral volume of distribution for erlotinib | V2,erlotinib/F | L/kg | 3.91 (0.554) |
Central volume of distribution for OSI-420 | V1,OSI420/F | L/kg | 0.0278 (0.316) |
Peripheral volume of distribution for OSI-420 | V2,OSI420/F | L/kg | 1.88 (0.047) |
Central volume of distribution for OSI-413 | V1,OSI413/F | L/kg | 0.00235 (0.359) |
Peripheral volume of distribution for OSI-413 | V2,OSI413/F | L/kg | 0.4 (0.0394) |
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Kim, T.H.; Shin, S.; Kim, S.; Bulitta, J.B.; Weon, K.-Y.; Joo, S.H.; Ma, E.; Yoo, S.D.; Park, G.-Y.; Kwon, D.R.; et al. Alterations in Pharmacokinetics of Gemcitabine and Erlotinib by Concurrent Administration of Hyangsayukgunja-Tang, a Gastroprotective Herbal Medicine. Molecules 2017, 22, 1515. https://doi.org/10.3390/molecules22091515
Kim TH, Shin S, Kim S, Bulitta JB, Weon K-Y, Joo SH, Ma E, Yoo SD, Park G-Y, Kwon DR, et al. Alterations in Pharmacokinetics of Gemcitabine and Erlotinib by Concurrent Administration of Hyangsayukgunja-Tang, a Gastroprotective Herbal Medicine. Molecules. 2017; 22(9):1515. https://doi.org/10.3390/molecules22091515
Chicago/Turabian StyleKim, Tae Hwan, Soyoung Shin, Sarah Kim, Jürgen B. Bulitta, Kwon-Yeon Weon, Sang Hoon Joo, Eunsook Ma, Sun Dong Yoo, Gi-Young Park, Dong Rak Kwon, and et al. 2017. "Alterations in Pharmacokinetics of Gemcitabine and Erlotinib by Concurrent Administration of Hyangsayukgunja-Tang, a Gastroprotective Herbal Medicine" Molecules 22, no. 9: 1515. https://doi.org/10.3390/molecules22091515