第五章 結 論
本 實 驗 是 以 方 便 、 快 速 、 簡 單 的 HPLC 條 件 來 定 量 血 漿 中 Cefaclor 濃度，此定量法需消耗大量溶媒，但可得到相當高的回收
LIII
率及相關係數之檢量線，其同日內及異日間之精密度及準確度也相當 高。本實驗不採用一般文獻記載傳統的萃取方式來進行血漿檢品的前 處理，也不以 Acetonitrule 等需經繁雜步驟的去蛋白方法，而是用 操作簡便迅速的酸(Trichloroacetic acid, TCA)來沉澱蛋白，作為 血漿檢品之前處理，此法可減低其他方法反覆移液所造成的誤差，而 經實驗後顯示此法並不比其他方法遜色。
在此實驗中須克服的最大難題便是，Cefaclor 於血漿中因 pH
＞5 以上所以不安定，故取受試者血液離心後，先加入 5μl 的磷酸 於 1000μl 的血漿中酸化，使其達到 pH 維持在 5 以下，以確保 Cefaclor 在血漿中可以呈現安定狀態，然後再儲存於－300C 的冷凍 櫃中。而實驗用的標準母液之泡製，也使用磷酸水使 Cefaclor 可以 維持在酸安定性下。經實驗結果得知，這樣的處理方式是合宜的。
口服 Keflor 膠囊劑 250mg 後，約 0.71±0.144 小時達到血中最 高濃度 5.55±0.417μg/ml；而服用 Kerfen 膠囊劑 250mg 後，經過 0.73±0.129 小時，達到血中最高濃度 5.54±0.401μg/ml；排除半 衰期則分別為 0.84±0.140 小時和 0.87±0.158 小時；曲線下面積則 為 6.91±0.908μg*hr/ml 和 6.83±0.792μg*hr/ml。國人服用 Keflor 和 Kerfen 後，測得的血中濃度及藥物動力學數據與國外相關 文獻比較並無很大差異。
以統計學 ANOVA 比較藥物動力學參數，包括 AUC0-8、AUC0-∞、Cmax、
Tmax、MRT 及 T1/2等均無統計上的差異(P＞0.05)，因此可證實 Kerfen 膠囊劑(永信藥廠)與 Kerfen 膠囊劑(台灣 Lilly 藥廠)具有生體相等 性。
表 1 受試者資料
編號 年齡(yr) 身高(cm) 體重(kg) 給藥次序 性別 A 26 166.9 67.9 Y L Male B 29 178.3 75.1 L Y Male
LIV
＊Y：Kerfen Yung Shin capsules(A0066C) B：Keflor Lilly,台灣 capsules(PL02)
表 2 血清中 Cefaclor 分析之標準曲線
表 2-1 Cefaclor 分析方法之標準曲線 Spike conc.
(ìg/ml)
Calibration curve of subject A
LV
Spike conc.
(ìg/ml)
Calibration curve of subject B Spike conc.
(ìg/ml)
Calibration curve of subject C
LVI
Spike conc.
(ìg/ml)
Calibration curve of subject D Spike conc.
(ìg/ml)
LVII
Calibration curve of subject E Spike conc.
(ìg/ml)
Calibration curve of subject F Spike conc.
(ìg/ml)
LVIII
Calibration curve of subject G Spike conc.
(ìg/ml)
Calibration curve of subject H Spike conc.
(ìg/ml)
LIX
Calibration curve of subject I Spike conc.
(ìg/ml)
Calibration curve of subject J Spike conc.
(ìg/ml)
LX
Calibration curve of subject K Spike conc.
(ìg/ml)
Calibration curve of subject L Spike conc.
(ìg/ml)
LXI
Peak High(mm) Cefaclor
LXII Cefaclor Conc.
(ìg/ml)
Plasma sample peak area ratio
Solvent sample peak area ratio
Recovery Time Cefaclor Conc. (ìg/ml)
LXIII Cefaclor Conc. (ìg/ml)
Time
LXIV
LXV
LXVI
表 4-1 Keflor(Lilly,台灣)與 Kerfen(永信)膠囊劑於 pH=1.2 溶離液 之溶離試驗
Keflor(Lilly,台灣)膠囊劑之溶離度
1 S1 S2 S3 S4 S5 S6 mean S.D. C.V.(%) 0 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 5 6.00 8.07 21.62 12.01 12.52 30.47 15.12 9.24 61.15 10 48.26 70.07 64.81 71.27 83.95 92.12 71.75 15.28 21.29 15 89.06 88.69 83.70 96.09 94.90 99.72 92.03 5.89 6.40 30 98.15 98.52 97.65 101.34 101.04 101.81 99.75 1.84 1.84 45 99.95 100.13 101.06 101.98 102.00 102.15 101.21 0.99 0.98 60 100.70 100.65 101.56 102.19 102.47 102.36 101.66 0.82 0.81 120 101.82 101.43 102.03 102.83 103.02 102.97 102.35 0.68 0.66
Kerfen(永信)膠囊劑之溶離度
時間
(min)
S1 S2 S3 S4 S5 S6 mean S.D. C.V.(%)
0 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00
5 98.19 77.10 93.63 68.30 96.92 93.59 87.96 12.27 13.95 10 101.69 96.62 100.61 96.24 97.86 95.69 98.12 2.48 2.53 15 102.05 96.93 100.96 96.54 98.57 95.89 98.49 2.52 2.56 30 102.92 97.65 101.59 97.00 99.08 96.24 99.08 2.66 2.69 45 103.34 98.00 101.93 97.38 99.32 96.51 99.41 2.70 2.71 60 103.91 98.45 102.32 97.69 99.52 96.81 99.78 2.78 2.78 120 104.76 99.22 103.11 98.42 100.04 97.39 100.49 2.86 2.84
表 4-2 Keflor(Lilly,台灣)與 Kerfen(永信)膠囊劑於 pH=4.5 溶離液 之溶離試驗
LXVII
Keflor(Lilly,台灣)膠囊劑之溶離度
時間
(min)
S1 S2 S3 S4 S5 S6 mean S.D. C.V.(%)
0 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00
5 21.31 19.56 19.51 20.11 26.12 17.57 20.70 2.92 14.10 10 83.02 67.89 77.76 69.63 81.47 82.19 76.99 6.65 8.64 15 100.25 93.66 95.67 93.98 97.24 90.85 95.28 3.24 3.41 30 101.25 98.14 99.24 98.83 98.41 96.47 98.72 1.56 1.58 45 101.59 99.43 100.23 101.09 100.19 98.63 100.19 1.08 1.07 60 101.80 99.90 100.60 101.76 100.73 98.81 100.60 1.14 1.13 120 102.38 100.79 101.19 102.29 101.86 100.70 101.54 0.74 0.73
Kerfen(永信)膠囊劑之溶離度
時間
(min)
S1 S2 S3 S4 S5 S6 mean S.D. C.V.(%)
0 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00
5 76.26 58.18 66.60 61.69 86.00 63.15 68.65 10.50 15.30 10 101.89 101.61 101.99 98.34 98.13 100.16 100.35 1.77 1.76 15 109.06 108.35 98.82 96.39 97.04 100.27 101.66 5.63 5.54 30 101.57 101.87 102.41 99.05 98.54 100.75 100.70 1.58 1.57 45 103.20 102.90 103.01 99.83 98.94 101.13 101.50 1.82 1.80 60 103.76 103.28 103.31 98.61 99.39 101.26 101.60 2.21 2.17 120 103.62 103.50 103.59 99.68 98.62 101.10 101.69 2.21 2.17
表 4-3 Keflor(Lilly,台灣)與 Kerfen(永信)膠囊劑於 pH=6.8 溶離 液之溶離試驗
LXVIII
Keflor(Lilly,台灣)膠囊劑之溶離度 時間
(min)
S1 S2 S3 S4 S5 S6 mean S.D. C.V.(%) 0 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00
5 19.00 20.21 3.81 8.03 6.72 8.06 10.97 6.87 62.66 10 73.98 71.22 72.44 65.85 74.27 63.85 70.27 4.38 6.24 15 103.36 100.23 99.55 93.97 98.26 94.64 98.34 3.55 3.61 30 109.18 107.14 106.95 104.36 106.81 105.91 106.73 1.58 1.48 45 118.93 114.53 116.65 115.17 108.73 108.08 113.68 4.36 3.84 60 111.70 109.63 109.65 108.78 109.52 110.12 109.90 0.98 0.89 120 110.94 110.03 110.73 110.42 111.22 113.31 111.11 1.15 1.04
Kerfen(永信)膠囊劑之溶離度
時間
(min)
S1 S2 S3 S4 S5 S6 mean S.D. C.V.(%)
0 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00
5 44.18 63.76 97.69 70.01 74.51 68.53 69.78 17.29 24.78 10 105.58 110.68 106.26 104.62 101.99 107.68 106.14 2.93 2.76 15 108.26 110.86 106.47 105.01 102.10 108.30 106.83 3.04 2.85 30 109.01 111.30 106.77 105.18 102.29 108.45 107.17 3.16 2.95 45 107.30 109.79 105.83 104.43 101.65 107.78 106.12 2.86 2.69 60 108.33 109.90 106.09 104.71 102.27 107.44 106.46 2.72 2.56 120 105.34 108.01 103.87 102.44 99.96 105.77 104.23 2.81 2.70
表 5 十二位受試者個別之血清中 Cefaclor 濃度
Subject A
LXIX
Time(hr) Keflor(ìg/ml) Kerfen(ìg/ml)
0.0 0 0
0.5 3.682 3.759
0.75 5.695 5.995
1.0 4.013 4.049
1.5 2.576 2.863
2 1.455 1.447
2.5 0.931 0.841
3 0.479 0.644
4 0.255 0.231
5 0.090 0.099
6 n.d. n.d.
8 n.d. n.d.
Subject B
Time(hr) Keflor(ìg/ml) Kerfen(ìg/ml)
0.0 0 0
0.5 3.448 3.498
0.75 5.757 5.482
1.0 3.626 4.017
1.5 1.832 2.350
2 1.045 1.161
2.5 0.697 0.758
3 0.390 0.515
4 0.198 0.245
5 0.104 0.107
6 n.d. n.d.
8 n.d. n.d.
Subject C
LXX
Time(hr) Keflor(ìg/ml) Kerfen(ìg/ml)
0.0 0 0
0.5 3.189 3.324
0.75 5.783 5.488
1.0 3.632 3.358
1.5 2.692 2.616
2 2.037 2.176
2.5 1.250 1.591
3 0.720 0.948
4 0.324 0.403
5 0.155 0.119
6 n.d. n.d.
8 n.d. n.d.
Subject D
Time(hr) Keflor(ìg/ml) Kerfen(ìg/ml)
0.0 0 0
0.5 3.643 3.914
0.75 5.102 5.152
1.0 3.003 2.600
1.5 1.796 1.929
2 1.098 1.217
2.5 0.824 0.768
3 0.430 0.469
4 0.241 0.217
5 0.103 0.101
6 n.d. n.d.
8 n.d. n.d.
Subject E
LXXI
Time(hr) Keflor(ìg/ml) Kerfen(ìg/ml)
0.0 0 0
0.5 6.189 5.754
0.75 4.436 4.428
1.0 3.163 3.118
1.5 2.410 1.932
2 1.393 1.248
2.5 0.832 0.718
3 0.501 0.406
4 0.257 0.237
5 0.094 0.092
6 n.d. n.d.
8 n.d. n.d.
Subject F
Time(hr) Keflor(ìg/ml) Kerfen(ìg/ml)
0.0 0 0
0.5 2.947 3.417
0.75 5.230 5.477
1.0 3.720 3.419
1.5 2.338 1.955
2 1.652 1.151
2.5 0.959. 0.636
3 0.540 0.377
4 0.310 0.152
5 0.104 0.082
6 n.d. n.d.
8 n.d. n.d.
Subject G
LXXII
Time(hr) Keflor(ìg/ml) Kerfen(ìg/ml)
0.0 0 0
0.5 5.110 5.211
0.75 3.517 3.403
1.0 2.212 2.144
1.5 1.252 1.255
2 0.749 0.802
2.5 0.419 0.543
3 0.293 0.325
4 0.143 0.171
5 0.093 0.103
6 n.d. n.d.
8 n.d. n.d.
Subject H
Time(hr) Keflor(ìg/ml) Kerfen(ìg/ml)
0.0 0 0
0.5 1.391 1.729
0.75 2.589 2.907
1.0 5.171 4.912
1.5 2.339 2.402
2 1.295 1.463
2.5 0.541 0.729
3 0.301 0.369
4 0.139 0.165
5 0.109 0.108
6 n.d. n.d.
8 n.d. n.d.
Subject I
LXXIII
Time(hr) Keflor(ìg/ml) Kerfen(ìg/ml)
0.0 0 0
0.5 3.832 3.749
0.75 5.659 5.882
1.0 4.011 3.734
1.5 2.581 2.224
2 1.923 1.339
2.5 1.137 0.877
3 0.643 0.518
4 0.311 0.282
5 0.103 0.102
6 n.d. n.d.
8 n.d. n.d.
Subject J
Time(hr) Keflor(ìg/ml) Kerfen(ìg/ml)
0.0 0 0
0.5 3.520 3.285
0.75 5.163 5.282
1.0 2.759 3.521
1.5 2.014 1.838
2 1.275 1.055
2.5 0.660 0.608
3 0.420 0.390
4 0.231 0.221
5 0.105 0.108
6 n.d. n.d.
8 n.d. n.d.
Subject K
LXXIV
Time(hr) Keflor(ìg/ml) Kerfen(ìg/ml)
0.0 0 0
0.5 6.301 2.794
0.75 4.689 6.358
1.0 3.101 4.168
1.5 1.930 2.394
2 1.283 1.343
2.5 0.838 0.775
3 0.421 0.352
4 0.265 0.178
5 0.084 0.087
6 n.d. n.d.
8 n.d. n.d.
Subject L
Time(hr) Keflor(ìg/ml) Kerfen(ìg/ml)
0.0 0 0
0.5 3.043 3.619
0.75 5.393 5.502
1.0 3.270 2.878
1.5 2.097 1.792
2 1.197 1.195
2.5 0.732 0.707
3 0.402 0.383
4 0.220 0.189
5 0.083 0.093
6 n.d. n.d.
8 n.d. n.d.
I
表 6 口服 Keflor(Lilly,台灣)250mg 膠囊劑之血清中 Cefaclor 濃度(ìg/ml)
Time(hr) A B C D E F G H I J K L Mean S.D. C.V.(%)
0.0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
0.5 3.682 3.448 3.189 3.643 6.189 2.947 5.110 1.391 3.832 3.520 6.301 3.043 3.858 1.393 36.117 0.75 5.695 5.757 5.783 5.102 4.436 5.230 3.517 2.589 5.659 5.163 4.689 5.393 4.918 0.986 20.048 1.0 4.013 3.626 3.632 3.003 3.163 3.720 2.212 5.171 4.011 2.759 3.101 3.270 3.473 0.749 21.565 1.5 2.576 1.832 2.692 1.796 2.410 2.338 1.252 2.339 2.581 2.014 1.930 2.097 2.155 0.416 19.295 2 1.455 1.045 2.037 1.098 1.393 1.652 0.749 1.295 1.923 1.275 1.283 1.197 1.367 0.364 26.608 2.5 0.931 0.697 1.250 0.824 0.832 0.959. 0.419 0.541 1.137 0.660 0.838 0.732 0.818 0.241 29.518 3 0.479 0.390 0.720 0.430 0.501 0.540 0.293 0.301 0.643 0.420 0.421 0.402 0.462 0.126 27.297 4 0.255 0.198 0.324 0.241 0.257 0.310 0.143 0.139 0.311 0.231 0.265 0.220 0.241 0.060 25.014 5 0.090 0.104 0.155 0.103 0.094 0.104 0.093 0.109 0.103 0.105 0.084 0.083 0.102 0.019 18.342 6 n.d. n.d. n.d. n.d. n.d. n.d. n.d. n.d. n.d. n.d. n.d. n.d. #VALUE! #DIV/0! #DIV/0!
8 n.d. n.d. n.d. n.d. n.d. n.d. n.d. n.d. n.d. n.d. n.d. n.d. #VALUE! #DIV/0! #DIV/0!
＊N.D. is expressed as not detectable.
II
表 7 口服 Kerfen(永信)250mg 膠囊劑之血清中 Cefaclor 濃度(ìg/ml)
Time(hr) A B C D E F G H I J K L Mean S.D. C.V.(%)
0.0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
0.5 3.759 3.498 3.324 3.914 5.754 3.417 5.211 1.729 3.749 3.285 2.794 3.619 3.671 1.031 28.082 0.75 5.995 5.482 5.488 5.152 4.428 5.477 3.403 2.907 5.882 5.282 6.358 5.502 5.113 1.034 20.231 1.0 4.049 4.017 3.358 2.600 3.118 3.419 2.144 4.912 3.734 3.521 4.168 2.878 3.493 0.755 21.617 1.5 2.863 2.350 2.616 1.929 1.932 1.955 1.255 2.402 2.224 1.838 2.394 1.792 2.129 0.432 20.276 2 1.447 1.161 2.176 1.217 1.248 1.151 0.802 1.463 1.339 1.055 1.343 1.195 1.3 0.329 25.291 2.5 0.841 0.758 1.591 0.768 0.718 0.636 0.543 0.729 0.877 0.608 0.775 0.707 0.796 0.267 33.597 3 0.644 0.515 0.948 0.469 0.406 0.377 0.325 0.369 0.518 0.390 0.352 0.383 0.475 0.174 36.723 4 0.231 0.245 0.403 0.217 0.237 0.152 0.171 0.165 0.282 0.221 0.178 0.189 0.224 0.068 30.379 5 0.099 0.107 0.119 0.101 0.092 0.082 0.103 0.108 0.102 0.108 0.087 0.093 0.1 0.010 10.264 6 n.d. n.d. n.d. n.d. n.d. n.d. n.d. n.d. n.d. n.d. n.d. n.d. #VALUE! #DIV/0! #DIV/0!
8 n.d. n.d. n.d. n.d. n.d. n.d. n.d. n.d. n.d. n.d. n.d. n.d. #VALUE! #DIV/0! #DIV/0!
＊N.D. is expressed as not detectable.
70
表 8 口服 Cefaclor 膠囊劑之平均血清中濃度(ìg/ml)
Time (hr)
Keflor (μg/ml)
Kerfen (μg/ml)
0.0 0 0
0.5 3.858±1.393 3.671±1.031 0.75 4.918±0.986 5.113±1.034 1.0 3.473±0.749 3.493±0.755 1.5 2.155±0.461 2.129±0.432 2 1.367±0.364 1.3±0.329 2.5 0.818±0.241 0.796±0.267
3 0.462±0.126 0.475±0.174 4 0.241±0.060 0.224±0.068 5 0.102±0.019 0.1±0.01
6 N.D. N.D.
8 N.D. N.D.
71
表 9 受試者口服 Keflor(Lilly,台灣)膠囊劑後於血清中之藥物動力學參數
Subject AUC0-10(ìg．
hr/ml)
AUC0-∞
(ìg．
hr/ml)
Cl/F (L/hr)
K (hr-1)
T1/2 (hr-1)
VDss/F (L)
MRT (hr)
Tmax (hr)
Cmax (ìg/ml) A 7.4494 7.5426 33.1606 0.9615 0.7209 34.4712 1.4184 0.7500 5.6947 B 6.4209 6.5790 38.0059 0.6593 1.0513 57.6435 1.4186 0.7500 5.7569 C 7.9352 8.1372 30.7307 0.7678 0.9028 40.0267 1.6273 0.7500 5.7826 D 6.2408 6.3646 39.3120 0.8296 0.8355 47.3872 1.4446 0.7500 5.1022 E 7.6130 7.7183 32.3884 0.8945 0.7749 36.2073 1.3544 0.5000 6.1886 F 7.0486 7.1655 34.8742 0.8935 0.7758 39.0319 1.5297 0.7500 5.2299 G 5.2446 5.3966 46.4103 0.6109 1.1347 75.9761 1.3217 0.5000 5.1096 H 5.6151 5.7245 44.0113 0.9936 0.6976 44.2939 1.4978 1.0000 5.1711 I 8.0220 8.1346 30.6994 0.9156 0.7571 33.5308 1.4998 0.7500 5.6587 J 6.2192 6.3667 39.2495 0.7144 0.9702 54.9388 1.4688 0.7500 5.1632 K 7.3458 7.4370 33.6171 0.9242 0.7500 36.3758 1.3141 0.5000 6.3007 L 6.2923 6.3833 39.1881 0.9124 0.7597 42.9521 1.4165 0.7500 5.3928 Mean 6.79 6.91 36.8 0.84 0.84 45.24 1.44 0.71 5.55 S.D. 0.909 0.908 5.085 0.124 0.140 12.367 0.090 0.144 0.417
C.V 13.393 13.146 13.818 14.733 16.699 27.336 6.263 20.329 7.519
72
表 10 受試者口服 Kerfen(永信)膠囊劑後於血清中之藥物動力學參數
Subject AUC0-10 (ìg．
hr/ml)
AUC0-∞
(ìg．
hr/ml)
Cl/F (L/hr)
K (hr-1)
T1/2 (hr-1)
VDss/F (L)
MRT (hr)
Tmax (hr)
Cmax (ìg/ml) A 7.7660 7.8777 31.7384 0.8896 0.7791 35.6752 1.4343 0.7500 5.9953 B 7.0076 7.1440 34.9862 0.7853 0.8827 44.5541 1.4449 0.7500 5.4817 C 8.2421 8.3589 29.8775 1.0187 0.6804 29.3289 1.6482 0.7500 5.4880 D 6.3073 6.4389 38.8275 0.7679 0.9027 50.5645 1.4450 0.7500 5.1520 E 6.9712 7.0721 35.3987 0.7679 0.7598 38.8025 1.3264 0.5000 5.7544 F 6.2785 6.3649 39.3800 0.9504 0.7294 41.4372 1.3425 0.7500 5.4771 G 5.3750 5.5535 45.0486 0.5754 1.2046 78.2875 1.3892 0.5000 5.2113 H 6.0107 6.1207 41.0720 0.9798 0.7075 41.9199 1.5213 1.0000 4.9123 I 7.2182 7.3348 34.0812 0.8755 0.7917 38.9277 1.4414 0.7500 5.8822 J 6.1912 6.3516 39.3518 0.6724 1.0308 58.5203 1.4474 0.7500 5.2823 K 6.9417 7.0662 35.3758 0.6988 0.9920 50.6257 1.4022 0.7500 6.3582 L 6.1821 6.3140 39.5944 0.7066 0.9809 56.0312 1.4111 0.7500 5.5017 Mean 6.71 6.83 37.06 0.81 0.87 47.06 1.44 0.73 5.54 S.D. 0.803 0.792 4.251 0.136 0.158 12.985 0.084 0.129 0.401
C.V 11.972 11.596 11.470 16.805 18.170 27.592 5.821 17.635 7.241
70
表 11 口服 Cefaclor 膠囊劑後之平均藥物動力學參數
Parameter Keflor(Lilly,台灣) Mean±S.D.
Kerfen(永信) Mean±S.D.
Statistic P＞0.05 AUC0-10 6.79±0.909 6.71±0.803 N.S.
AUC0-∞1 6.91±0.908 6.83±0.792 N.S Cl/F 36.8±5.085 37.06±4.251 N.S K 0.84±0.124 0.81±0.136 N.S T1/2 0.84±0.140 0.87±0.158 N.S VDss/F 45.24±12.367 47.06±12.985 N.S MRT 1.44±0.090 1.44±0.084 N.S Tmax 0.71±0.144 0.73±0.129 N.S Cmax 5.55±0.417 5.54±0.401 N.S
71
表 12 ANOVA 統計學比較
Subject：受試者編號
Period：代表兩個服藥週期Ⅰ及Ⅱ
Form：代表 L(Keflor capsule)及 Y(Kerfen capsule)
ANOVA Table for Cmax
Effect SS df MS F Probability Subject 3.355315 11 0.305029 12.42 0.0002
Period 0.085105 1 0.085105 3.47 0.0923 Form 0.000123 1 0.000123 0.01 0.9449 Error 0.245553 10 0.024555
ANOVA Table for Tmax
Effect SS df MS F Probability Subject 0.382812 11 0.034801 13.36 0.0001
Period 0.002604 1 0.002604 1.00 0.3409 Form 0.002604 1 0.002604 1.00 0.3409 Error 0.026042 10 0.002604
ANOVA Table for MRT
Effect SS df MS F Probability Subject 0.139916 11 0.012720 5.18 0.0074
Period 0.002311 1 0.002311 0.94 0.3548 Form 0.000141 1 0.000141 0.06 0.8156 Error 0.024544 10 0.002454
72
ANOVA Table for AUCall
Effect SS df MS F Probability Subject 14.961624 11 1.360148 11.34 0.0003
Period 0.034138 1 0.034138 0.28 0.6054 Form 0.038021 1 0.038021 0.32 0.5859 Error 1.199651 10 0.119965
ANOVA Table for AUCinf
Effect SS df MS F Probability Subject 14.760857 11 1.341896 11.39 0.0003
Period 0.038353 1 0.038353 0.33 0.5809 Form 0.037810 1 0.037810 0.32 0.5835 Error 1.178130 10 0.117813
ANOVA Table for Cl/F
Effect SS df MS F Probability Subject 441.630105 11 40.148191 13.34 0.0001
Period 1.552842 1 1.552842 0.52 0.4891 Form 0.417967 1 0.417967 0.14 0.7172 Error 30.104331 10 3.010433
73
ANOVA Table for V/F
Effect SS df MS F Probability Subject 3181.068274 11 289.188025 8.35 0.0011
Period 1.232888 1 1.232888 0.04 0.8541 Form 20.044710 1 20.044710 0.58 0.4644 Error 346.323648 10 34.632365
ANOVA Table for K
Effect SS df MS F Probability Subject 0.287827 11 0.026166 2.87 0.0539
Period 0.000988 1 0.000988 0.11 0.7488 Form 0.002491 1 0.002491 0.27 0.6126 Error 0.091168 10 0.009117
ANOVA Table for T1/2
Effect SS df MS F Probability Subject 0.392631 11 0.035694 3.63 0.0259
Period 0.000272 1 0.000272 0.03 0.8714 Form 0.004027 1 0.004027 0.41 0.536 Error 0.098430 10 0.009843
74
表 13 分析所得參數的 ANOVA 統計分析
Parameter F 90%C.I. Power P-value Cmax 0.00 97.83~102.01 1.0000 0.0000 Tmax 0.07 97.61~108.27 0.9995 0.0001 MRT 0.001 97.12~102.21 1.0000 0.0000 AUCall 0.03 95.05~102.60 1.0000 0.0000 AUCinf 0.03 95.18~102.53 1.0000 0.0000 Cl/F 0.01 97.23~104.21 1.0000 0.0000 V/F 0.07 94.41~113.68 0.9220 0.0061 K 0.10 89.16~105.99 0.9679 0.0014 T1/2 0.11 94.37~111.77 0.9595 0.0024
1. ANOVA of F(1,10) at P=0.05 is 4.96.
2. The 90%C.I. is classical 90% Confidence Interval.
3. 1-bata=Power
4. The P-value is probability value estimated form two-one side t-test.
75
圖 1 Keflor 和 Kerfen 在不同 pH 之溶離試驗曲線圖
圖 1 - 1 兩 種 C e f a c l o r 膠 囊 劑 在 p H 1 . 2 H C l 中 的 溶 離 曲 線
Time(min)
0 20 40 60 80 100 120 140
Dissolved(%)
0 20 40 60 80 100 120
Keflor Kerfen
圖 1-2 兩種 Cefaclor 膠囊劑在 pH 4.5 Phosphate Buffer 中的溶離曲線
Time(min)
0 20 40 60 80 100 120 140
Dissolved(%)
0 20 40 60 80 100 120
Keflor Kerfen
76
圖 1-3 兩種 Cefaclor 膠囊劑在 pH 6.8 Phosphate Buffer 中的溶離曲線
Time(min)
0 20 40 60 80 100 120 140
Dissolved(%)
0 20 40 60 80 100 120
Keflor Kerfen
77
圖 2 Cefaclor 之高效液相層析法
(1) (2)
(3) (4)
(1) Blank serum
(2) Blank serum and â-Hydroxyethyl-theophylline (3) Blank serum and Cefaclor
(4) Blank serum、Cefaclor and â-Hydroxyethyl-theophylline
24.42
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 Retention Time (min)
-1
Intensity (mV) 21.02 24.44
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 Retention Time (min)
-1 Retention Time (min)
-1
Intensity (mV) 20.91 23.65
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 Retention Time (min)
-1
78
圖 3 Keflor 與 Kerfen 之生體相等性之總標準檢量線
Calibration Curve of Cefaclor
Y=0.25878X+0.001238 r2=0.9997
Conc.(µg/ml)
0 2 4 6 8 10 12
Peak area ratio
0 2 4 6 8 10 12
79
圖 4 Keflor 與 Kerfen 生體可用率比較之個別標準檢量線
Subject A
Y=0.235948X+0.011251 r2=0.99992
Conc.(µg/ml)
0 2 4 6 8 10 12
Peak area ratio
0 1 2 3
Subject B
Y=0.240755X+0.000388 r2=0.99991
Conc.(µg/ml)
0 2 4 6 8 10 12
Peak area ratio
0 1 2 3
80 Subject C Y=0.254597X-0.00599 r2=0.99998
Conc.(µg/ml)
0 2 4 6 8 10 12
Peak area ratio
0 1 2 3
Subject D Y=0.244933X-0.00798 r2=0.99996
Conc.(µg/ml)
0 2 4 6 8 10 12
Peak area ratio
0 1 2 3
81 Subject E Y=0.229441X+0.002096 r2=0.9993
Conc.(µg/ml)
0 2 4 6 8 10 12
Peak area ratio
0 1 2 3
Subject F Y=0.21447X+0.001086 r2=0.99991
Conc.(µg/ml)
0 2 4 6 8 10 12
Peak area ratio
0 1 2 3
82 Subject G Y=0.228782X-0.00399 r2=0.99990
Conc.(µg/ml)
0 2 4 6 8 10 12
Peak area ratio
0 1 2 3
Subject H Y=0.228104X-0.02176 r2=0.99970
Conc.(µg/ml)
0 2 4 6 8 10 12
Peak area ratio
0 1 2 3
83 Subject I Y=0.220743X-0.01258 r2=0.99997
Conc.(µg/ml)
0 2 4 6 8 10 12
Peak area ratio
0 1 2 3
Subject J Y=0.233687X-0.01878 r2=0.99999
Conc.(µg/ml)
0 2 4 6 8 10 12
Peak area ratio
0 1 2 3
84 Subject K
Y=0.201283X+0.004224 r2=0.99936
Conc.(µg/ml)
0 2 4 6 8 10 12
Peak area ratio
0 1 2 3
Subject L
Y=0.211762X+0.006789 r2=0.99951
Conc.(µg/ml)
0 2 4 6 8 10 12
Peak area ratio
0 1 2 3
85
圖 5 Keflor 與 Kerfen 於個別受試者血清中 Cefaclor 之濃度曲線圖
Subject A
Time(hr)
0 2 4 6 8 10
Conc.(µg/ml)
0 1 2 3 4 5 6 7
Keflor Kerfen
Subject B
Time(hr)
0 2 4 6 8 10
Conc.(ug/ml)
0 1 2 3 4 5 6 7
Keflor Kerfen
86 Subject C
Time(hr)
0 2 4 6 8 10
Conc.(ug/ml)
0 1 2 3 4 5 6 7
Keflor Kerfen
Subject D
Time(hr)
0 2 4 6 8 10
Conc.(ug/ml)
0 1 2 3 4 5 6
Keflor Kerfen
87 Subject E
Time(hr)
0 2 4 6 8 10
Conc.(ug/ml)
0 1 2 3 4 5 6 7
Subject F
Time(hr)
0 2 4 6 8 10
Conc.(µg/ml)
0 1 2 3 4 5 6
Keflor Kerfen
88 Subject G
Time(hr)
0 2 4 6 8 10
Conc.(ug/ml)
0 1 2 3 4 5 6
Keflor Kerfen
Subject H
X Data
0 2 4 6 8 10
Conc.(ug/ml)
0 1 2 3 4 5 6
Keflor Kerfen
89 Subject I
X Data
0 2 4 6 8 10
Y Data
0 1 2 3 4 5 6 7
Keflor Kerfen
Subject J
Time(hr)
0 2 4 6 8 10
Conc.(ug/ml)
0 1 2 3 4 5 6
Keflor Kerfen
90 Subject K
Time(hr)
0 2 4 6 8 10
Conc.(ug/ml)
0 1 2 3 4 5 6 7
Keflor Kerfen
Subject L
Time(hr)
0 2 4 6 8 10
Conc.(ug/ml)
0 1 2 3 4 5 6
Keflor Kerfen
91
圖 6 Keflor 與 Kerfen 於受試者血清中 Cefaclor 之平均血中濃度曲線圖
Time(hr)
0 2 4 6 8 10
Conc.(µg/ml)
0 1 2 3 4 5 6 7
Keflor Kerfen
92
圖 7 Keflor 與 Kerfen 於個別受試者血清中 Cefaclor 之 log 濃度曲線圖
Subject A
Time(hr)
0 2 4 6 8 10
Log conc.(µg/ml)
0.01 0.1 1 10
Keflor Kerfen
Subject B
Time(hr)
0 2 4 6 8 10
Log conc.(µg/ml)
0.01 0.1 1 10
Keflor Kerfen
93 Subject C
Time(hr)
0 2 4 6 8 10
Log conc.(µg/ml)
0.01 0.1 1 10
Keflor Kerfen
Subject D
Time(hr)
0 2 4 6 8 10
Log conc.(µg.ml)
0.01 0.1 1 10
Keflor Kerfen
94 Subject E
Time(hr)
0 2 4 6 8 10
Log conc.(µg/ml)
0.01 0.1 1 10
Keflor Kerfen
Subject F
Time(hr)
0 2 4 6 8 10
Log conc.(µg/ml)
0.01 0.1 1 10
Keflor Kerfen
95 Subject G
Time(hr)
0 2 4 6 8 10
Log conc.(µg/ml)
0.01 0.1 1 10
Keflor Kerfen
Subject H
Time(hr)
0 2 4 6 8 10
Log conc.(µg/ml)
0.01 0.1 1 10
Keflor Kerfen
96 Subject I
Time(hr))
0 2 4 6 8 10
Log conc.(µg/ml)
0.01 0.1 1 10
Keflor Kerfen
Subject J
Time(hr)
0 2 4 6 8 10
Log conc.(µg/ml)
0.01 0.1 1 10
Keflor Kerfen
97 Subject K
Time(hr)
0 2 4 6 8 10
Log conc.(µg/ml)
0.01 0.1 1 10
Keflor Kerfen
Subject L
Time(hr)
0 2 4 6 8 10
Log conc.(µg/ml)
0.01 0.1 1 10
Keflor Kerfen
98
圖 8 Keflor 與 Kerfen 於受試者血清中 Cefaclor 之平均血中 log 濃度圖
Time(hr)
0 2 4 6 8 10
Log conc.(µg/ml)
0.01 0.1 1 10
Keflor Kerfen
99
附錄一
非室模式(Non compartment model)
藥物動力學參數說明：
AUC0-8：血中藥物濃度對時間曲線，時間從 0 到最後抽血點之曲線下 面積 (ìg*min/ml)。
AUC0-8 = ∫Cpdt
AUC0-∞：血中藥物濃度對時間曲線，時間從 0 到無限大之曲線下面積 (ìg*min/ml)。
AUC0-∞ = ∫Cpdt
Cmax：投藥後所到達的最高血中濃度 (ìg/ml)。
Tmax：投藥後到達最高血中濃度的時間 (hr)。
100
Cl/F：藥物的清除率 (L/hr)。
Cl / F = Dose / ∫AUC
K：藥物的排除速率常數(hr-1)。
T1/2：藥物之末端排除半衰期 (hr)。
T1/2 = 0.693 / K
VDSS/F：體內藥物分布達穩定狀態之分佈體積 (L)。
VDSS / F = Dose / K ×∫AUC
MRT：藥物之平均滯留時間 (hr)。
AUCssinf：為達穩定狀態時，給藥時間至無限大時間之血中藥物濃度對 時間曲線下面積。
AUCinf＝AUClast＋Clast/K
AUC AUMC
dt C txCpdt
MRT = ∫ ∫ =
∫
∞
∞
∞
0 0
0
101
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