Note
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Preclinical - effect on liver function of 6 test drugs#
This example illustrates the use of Liver for fitting of signals
measured in liver. The use case is provided by the liver work package of the
TRISTAN project which develops imaging
biomarkers for drug safety assessment. The data and analysis were first
published in Melillo et al (2023).
The specific objective of the study was to determine the effect of selected drugs on hepatocellular uptake and excretion of the liver-specific contrast agent gadoxetate. If a drug inhibits uptake into liver cells, then it might cause other drugs to circulate in the blood stream for longer than expected, potentially causing harm to other organs. Alternatively, if a drug inhibits excretion from the liver, then it might cause other drugs to pool in liver cells for much longer than expected, potentially causing liver injury. These so-called drug-drug interactions (DDI’s) pose a significant risk to patients and trial participants. A direct in-vivo measurement of drug effects on liver uptake and excretion can potentially help improve predictions of DDI’s and inform dose setting strategies to reduce the risk.
The study presented here measured gadoxetate uptake and excretion in healthy rats before and after injection of 6 test drugs. Studies were performed in preclinical MRI scanners at 3 different centers and 2 different field strengths. Results demonstrated that two of the tested drugs (rifampicin and cyclosporine) showed strong inhibition of both uptake and excretion. One drug (ketoconazole) inhibited uptake but not excretion. Three drugs (pioglitazone, bosentan and asunaprevir) inhibited excretion but not uptake.
Reference
Melillo N, Scotcher D, Kenna JG, Green C, Hines CDG, Laitinen I, Hockings PD, Ogungbenro K, Gunwhy ER, Sourbron S, et al. Use of In Vivo Imaging and Physiologically-Based Kinetic Modelling to Predict Hepatic Transporter Mediated Drug–Drug Interactions in Rats. Pharmaceutics. 2023; 15(3):896. [DOI]
Setup#
Model definition#
In order to avoid some repetition in this script, we define a function that returns a trained model for a single dataset.
The model uses a standardized, population-average input function and fits for only 2 parameters, fixing all other free parameters to typical values for this rat model:
def tristan_rat(roi, par, **kwargs):
# High-resolution time points for prediction
t = np.arange(0, np.amax(roi['time'])+0.5, 0.5)
# Standard input function
ca = dc.aif_tristan_rat(t, BAT=par['BAT'], duration=par['duration'])
# Liver model with population input function
model = dc.Liver(
# Input parameters
t = t,
ca = ca,
# Acquisition parameters
field_strength = par['field_strength'],
TR = par['TR'],
FA = par['FA'],
n0 = par['n0'],
# Configure as in the TRISTAN-rat study
config = 'TRISTAN-rat',
)
return model.train(roi['time'], roi['liver'], **kwargs)
Check model fit#
Before running the full analysis on all cases, lets illustrate the results by fitting the baseline visit for the first subject. We use maximum verbosity to get some feedback about the iterations:
Iteration Total nfev Cost Cost reduction Step norm Optimality
0 1 4.0626e+01 8.81e+03
1 3 2.4807e+01 1.58e+01 4.50e+02 1.52e+03
2 5 2.0845e+01 3.96e+00 3.37e+02 9.12e+02
3 6 1.3832e+01 7.01e+00 5.84e+02 2.96e+03
4 7 5.7140e+00 8.12e+00 3.67e+01 3.14e+02
5 8 3.7094e+00 2.00e+00 1.86e+02 1.14e+03
6 9 2.3659e-01 3.47e+00 1.61e+01 1.08e+02
7 10 1.9487e-01 4.17e-02 3.04e+00 1.85e-02
8 11 1.9487e-01 3.25e-06 1.01e-01 8.95e-04
`xtol` termination condition is satisfied.
Function evaluations 11, initial cost 4.0626e+01, final cost 1.9487e-01, first-order optimality 8.95e-04.
Plot the results to check that the model has fitted the data:
Print the measured model parameters and any derived parameters and check that standard deviations of measured parameters are small relative to the value, indicating that the parameters are measured reliably:
model.print_params(round_to=3)
--------------------------------
Free parameters with their stdev
--------------------------------
Hepatocellular uptake rate (khe): 0.029 (0.001) mL/sec/cm3
Hepatocellular mean transit time (Th): 192.246 (4.837) sec
----------------------------
Fixed and derived parameters
----------------------------
Hematocrit (H): 0.418
Liver extracellular volume fraction (ve): 0.23 mL/cm3
Biliary tissue excretion rate (Kbh): 0.005 mL/sec/cm3
Hepatocellular tissue uptake rate (Khe): 0.127 mL/sec/cm3
Biliary excretion rate (kbh): 0.004 mL/sec/cm3
Liver extraction fraction (E): 0.57
Hepatic plasma clearance (Ktrans): 0.013 mL/sec/cm3
Fit all data#
Now that we have illustrated an individual result in some detail, we proceed with fitting all the data. Results are stored in a dataframe in long format:
results = []
# Loop over all datasets
for subj in rois.keys():
for visit in rois[subj].keys():
roi = rois[subj][visit]
par = pars[subj][visit]
# Generate a trained model
model = tristan_rat(roi, par, xtol=1e-3)
# Export fitted parameters as lists
rows = model.export_params(type='list')
# Add study, visit and subject info
rows = [row + [par['study'], par['visit'], subj] for row in rows]
# Add to the list of all results
results += rows
# Combine all results into a single dataframe.
cols = ['parameter', 'name', 'value', 'unit', 'stdev', 'study',
'visit', 'subject']
results = pd.DataFrame(results, columns=cols)
# Print all results
print(results.to_string())
parameter name value unit stdev study visit subject
0 H Hematocrit 0.418000 0.000000 5 1 S05-02
1 ve Liver extracellular volume fraction 0.230000 mL/cm3 0.000000 5 1 S05-02
2 khe Hepatocellular uptake rate 0.029190 mL/sec/cm3 0.000690 5 1 S05-02
3 Th Hepatocellular mean transit time 192.246433 sec 4.836834 5 1 S05-02
4 Kbh Biliary tissue excretion rate 0.005202 mL/sec/cm3 0.000000 5 1 S05-02
5 Khe Hepatocellular tissue uptake rate 0.126911 mL/sec/cm3 0.000000 5 1 S05-02
6 kbh Biliary excretion rate 0.004005 mL/sec/cm3 0.000000 5 1 S05-02
7 E Liver extraction fraction 0.570014 0.000000 5 1 S05-02
8 Ktrans Hepatic plasma clearance 0.012551 mL/sec/cm3 0.000000 5 1 S05-02
9 H Hematocrit 0.418000 0.000000 5 2 S05-02
10 ve Liver extracellular volume fraction 0.230000 mL/cm3 0.000000 5 2 S05-02
11 khe Hepatocellular uptake rate 0.017053 mL/sec/cm3 0.000899 5 2 S05-02
12 Th Hepatocellular mean transit time 316.554650 sec 19.042915 5 2 S05-02
13 Kbh Biliary tissue excretion rate 0.003159 mL/sec/cm3 0.000000 5 2 S05-02
14 Khe Hepatocellular tissue uptake rate 0.074145 mL/sec/cm3 0.000000 5 2 S05-02
15 kbh Biliary excretion rate 0.002432 mL/sec/cm3 0.000000 5 2 S05-02
16 E Liver extraction fraction 0.436457 0.000000 5 2 S05-02
17 Ktrans Hepatic plasma clearance 0.009610 mL/sec/cm3 0.000000 5 2 S05-02
18 H Hematocrit 0.418000 0.000000 5 1 S05-03
19 ve Liver extracellular volume fraction 0.230000 mL/cm3 0.000000 5 1 S05-03
20 khe Hepatocellular uptake rate 0.023123 mL/sec/cm3 0.002281 5 1 S05-03
21 Th Hepatocellular mean transit time 154.454455 sec 16.290498 5 1 S05-03
22 Kbh Biliary tissue excretion rate 0.006474 mL/sec/cm3 0.000000 5 1 S05-03
23 Khe Hepatocellular tissue uptake rate 0.100536 mL/sec/cm3 0.000000 5 1 S05-03
24 kbh Biliary excretion rate 0.004985 mL/sec/cm3 0.000000 5 1 S05-03
25 E Liver extraction fraction 0.512232 0.000000 5 1 S05-03
26 Ktrans Hepatic plasma clearance 0.011279 mL/sec/cm3 0.000000 5 1 S05-03
27 H Hematocrit 0.418000 0.000000 5 2 S05-03
28 ve Liver extracellular volume fraction 0.230000 mL/cm3 0.000000 5 2 S05-03
29 khe Hepatocellular uptake rate 0.010411 mL/sec/cm3 0.000681 5 2 S05-03
30 Th Hepatocellular mean transit time 385.263252 sec 30.439907 5 2 S05-03
31 Kbh Biliary tissue excretion rate 0.002596 mL/sec/cm3 0.000000 5 2 S05-03
32 Khe Hepatocellular tissue uptake rate 0.045265 mL/sec/cm3 0.000000 5 2 S05-03
33 kbh Biliary excretion rate 0.001999 mL/sec/cm3 0.000000 5 2 S05-03
34 E Liver extraction fraction 0.321029 0.000000 5 2 S05-03
35 Ktrans Hepatic plasma clearance 0.007069 mL/sec/cm3 0.000000 5 2 S05-03
36 H Hematocrit 0.418000 0.000000 5 1 S05-04
37 ve Liver extracellular volume fraction 0.230000 mL/cm3 0.000000 5 1 S05-04
38 khe Hepatocellular uptake rate 0.017874 mL/sec/cm3 0.000788 5 1 S05-04
39 Th Hepatocellular mean transit time 185.344175 sec 8.871480 5 1 S05-04
40 Kbh Biliary tissue excretion rate 0.005395 mL/sec/cm3 0.000000 5 1 S05-04
41 Khe Hepatocellular tissue uptake rate 0.077715 mL/sec/cm3 0.000000 5 1 S05-04
42 kbh Biliary excretion rate 0.004154 mL/sec/cm3 0.000000 5 1 S05-04
43 E Liver extraction fraction 0.448054 0.000000 5 1 S05-04
44 Ktrans Hepatic plasma clearance 0.009866 mL/sec/cm3 0.000000 5 1 S05-04
45 H Hematocrit 0.418000 0.000000 5 2 S05-04
46 ve Liver extracellular volume fraction 0.230000 mL/cm3 0.000000 5 2 S05-04
47 khe Hepatocellular uptake rate 0.015201 mL/sec/cm3 0.000948 5 2 S05-04
48 Th Hepatocellular mean transit time 205.798967 sec 14.080670 5 2 S05-04
49 Kbh Biliary tissue excretion rate 0.004859 mL/sec/cm3 0.000000 5 2 S05-04
50 Khe Hepatocellular tissue uptake rate 0.066089 mL/sec/cm3 0.000000 5 2 S05-04
51 kbh Biliary excretion rate 0.003742 mL/sec/cm3 0.000000 5 2 S05-04
52 E Liver extraction fraction 0.408402 0.000000 5 2 S05-04
53 Ktrans Hepatic plasma clearance 0.008993 mL/sec/cm3 0.000000 5 2 S05-04
54 H Hematocrit 0.418000 0.000000 5 1 S05-05
55 ve Liver extracellular volume fraction 0.230000 mL/cm3 0.000000 5 1 S05-05
56 khe Hepatocellular uptake rate 0.015750 mL/sec/cm3 0.001193 5 1 S05-05
57 Th Hepatocellular mean transit time 194.627433 sec 16.106847 5 1 S05-05
58 Kbh Biliary tissue excretion rate 0.005138 mL/sec/cm3 0.000000 5 1 S05-05
59 Khe Hepatocellular tissue uptake rate 0.068477 mL/sec/cm3 0.000000 5 1 S05-05
60 kbh Biliary excretion rate 0.003956 mL/sec/cm3 0.000000 5 1 S05-05
61 E Liver extraction fraction 0.417006 0.000000 5 1 S05-05
62 Ktrans Hepatic plasma clearance 0.009182 mL/sec/cm3 0.000000 5 1 S05-05
63 H Hematocrit 0.418000 0.000000 5 2 S05-05
64 ve Liver extracellular volume fraction 0.230000 mL/cm3 0.000000 5 2 S05-05
65 khe Hepatocellular uptake rate 0.014848 mL/sec/cm3 0.000687 5 2 S05-05
66 Th Hepatocellular mean transit time 257.645715 sec 13.315206 5 2 S05-05
67 Kbh Biliary tissue excretion rate 0.003881 mL/sec/cm3 0.000000 5 2 S05-05
68 Khe Hepatocellular tissue uptake rate 0.064556 mL/sec/cm3 0.000000 5 2 S05-05
69 kbh Biliary excretion rate 0.002989 mL/sec/cm3 0.000000 5 2 S05-05
70 E Liver extraction fraction 0.402744 0.000000 5 2 S05-05
71 Ktrans Hepatic plasma clearance 0.008868 mL/sec/cm3 0.000000 5 2 S05-05
72 H Hematocrit 0.418000 0.000000 5 1 S05-06
73 ve Liver extracellular volume fraction 0.230000 mL/cm3 0.000000 5 1 S05-06
74 khe Hepatocellular uptake rate 0.017684 mL/sec/cm3 0.001342 5 1 S05-06
75 Th Hepatocellular mean transit time 171.878130 sec 14.125022 5 1 S05-06
76 Kbh Biliary tissue excretion rate 0.005818 mL/sec/cm3 0.000000 5 1 S05-06
77 Khe Hepatocellular tissue uptake rate 0.076888 mL/sec/cm3 0.000000 5 1 S05-06
78 kbh Biliary excretion rate 0.004480 mL/sec/cm3 0.000000 5 1 S05-06
79 E Liver extraction fraction 0.445411 0.000000 5 1 S05-06
80 Ktrans Hepatic plasma clearance 0.009808 mL/sec/cm3 0.000000 5 1 S05-06
81 H Hematocrit 0.418000 0.000000 5 2 S05-06
82 ve Liver extracellular volume fraction 0.230000 mL/cm3 0.000000 5 2 S05-06
83 khe Hepatocellular uptake rate 0.019304 mL/sec/cm3 0.001365 5 2 S05-06
84 Th Hepatocellular mean transit time 208.105645 sec 16.012430 5 2 S05-06
85 Kbh Biliary tissue excretion rate 0.004805 mL/sec/cm3 0.000000 5 2 S05-06
86 Khe Hepatocellular tissue uptake rate 0.083928 mL/sec/cm3 0.000000 5 2 S05-06
87 kbh Biliary excretion rate 0.003700 mL/sec/cm3 0.000000 5 2 S05-06
88 E Liver extraction fraction 0.467143 0.000000 5 2 S05-06
89 Ktrans Hepatic plasma clearance 0.010286 mL/sec/cm3 0.000000 5 2 S05-06
90 H Hematocrit 0.418000 0.000000 10 1 S10-01
91 ve Liver extracellular volume fraction 0.230000 mL/cm3 0.000000 10 1 S10-01
92 khe Hepatocellular uptake rate 0.032653 mL/sec/cm3 0.002459 10 1 S10-01
93 Th Hepatocellular mean transit time 204.095965 sec 16.306195 10 1 S10-01
94 Kbh Biliary tissue excretion rate 0.004900 mL/sec/cm3 0.000000 10 1 S10-01
95 Khe Hepatocellular tissue uptake rate 0.141969 mL/sec/cm3 0.000000 10 1 S10-01
96 kbh Biliary excretion rate 0.003773 mL/sec/cm3 0.000000 10 1 S10-01
97 E Liver extraction fraction 0.597252 0.000000 10 1 S10-01
98 Ktrans Hepatic plasma clearance 0.013151 mL/sec/cm3 0.000000 10 1 S10-01
99 H Hematocrit 0.418000 0.000000 10 2 S10-01
100 ve Liver extracellular volume fraction 0.230000 mL/cm3 0.000000 10 2 S10-01
101 khe Hepatocellular uptake rate 0.010368 mL/sec/cm3 0.000343 10 2 S10-01
102 Th Hepatocellular mean transit time 409.183856 sec 16.626224 10 2 S10-01
103 Kbh Biliary tissue excretion rate 0.002444 mL/sec/cm3 0.000000 10 2 S10-01
104 Khe Hepatocellular tissue uptake rate 0.045078 mL/sec/cm3 0.000000 10 2 S10-01
105 kbh Biliary excretion rate 0.001882 mL/sec/cm3 0.000000 10 2 S10-01
106 E Liver extraction fraction 0.320129 0.000000 10 2 S10-01
107 Ktrans Hepatic plasma clearance 0.007049 mL/sec/cm3 0.000000 10 2 S10-01
108 H Hematocrit 0.418000 0.000000 10 1 S10-02
109 ve Liver extracellular volume fraction 0.230000 mL/cm3 0.000000 10 1 S10-02
110 khe Hepatocellular uptake rate 0.025971 mL/sec/cm3 0.001777 10 1 S10-02
111 Th Hepatocellular mean transit time 260.964310 sec 19.500936 10 1 S10-02
112 Kbh Biliary tissue excretion rate 0.003832 mL/sec/cm3 0.000000 10 1 S10-02
113 Khe Hepatocellular tissue uptake rate 0.112917 mL/sec/cm3 0.000000 10 1 S10-02
114 kbh Biliary excretion rate 0.002951 mL/sec/cm3 0.000000 10 1 S10-02
115 E Liver extraction fraction 0.541175 0.000000 10 1 S10-02
116 Ktrans Hepatic plasma clearance 0.011916 mL/sec/cm3 0.000000 10 1 S10-02
117 H Hematocrit 0.418000 0.000000 10 2 S10-02
118 ve Liver extracellular volume fraction 0.230000 mL/cm3 0.000000 10 2 S10-02
119 khe Hepatocellular uptake rate 0.027056 mL/sec/cm3 0.001882 10 2 S10-02
120 Th Hepatocellular mean transit time 345.740734 sec 27.331373 10 2 S10-02
121 Kbh Biliary tissue excretion rate 0.002892 mL/sec/cm3 0.000000 10 2 S10-02
122 Khe Hepatocellular tissue uptake rate 0.117634 mL/sec/cm3 0.000000 10 2 S10-02
123 kbh Biliary excretion rate 0.002227 mL/sec/cm3 0.000000 10 2 S10-02
124 E Liver extraction fraction 0.551318 0.000000 10 2 S10-02
125 Ktrans Hepatic plasma clearance 0.012139 mL/sec/cm3 0.000000 10 2 S10-02
126 H Hematocrit 0.418000 0.000000 10 1 S10-03
127 ve Liver extracellular volume fraction 0.230000 mL/cm3 0.000000 10 1 S10-03
128 khe Hepatocellular uptake rate 0.036772 mL/sec/cm3 0.002993 10 1 S10-03
129 Th Hepatocellular mean transit time 192.094645 sec 16.432004 10 1 S10-03
130 Kbh Biliary tissue excretion rate 0.005206 mL/sec/cm3 0.000000 10 1 S10-03
131 Khe Hepatocellular tissue uptake rate 0.159880 mL/sec/cm3 0.000000 10 1 S10-03
132 kbh Biliary excretion rate 0.004008 mL/sec/cm3 0.000000 10 1 S10-03
133 E Liver extraction fraction 0.625472 0.000000 10 1 S10-03
134 Ktrans Hepatic plasma clearance 0.013772 mL/sec/cm3 0.000000 10 1 S10-03
135 H Hematocrit 0.418000 0.000000 10 2 S10-03
136 ve Liver extracellular volume fraction 0.230000 mL/cm3 0.000000 10 2 S10-03
137 khe Hepatocellular uptake rate 0.033378 mL/sec/cm3 0.001953 10 2 S10-03
138 Th Hepatocellular mean transit time 253.681764 sec 15.936704 10 2 S10-03
139 Kbh Biliary tissue excretion rate 0.003942 mL/sec/cm3 0.000000 10 2 S10-03
140 Khe Hepatocellular tissue uptake rate 0.145124 mL/sec/cm3 0.000000 10 2 S10-03
141 kbh Biliary excretion rate 0.003035 mL/sec/cm3 0.000000 10 2 S10-03
142 E Liver extraction fraction 0.602527 0.000000 10 2 S10-03
143 Ktrans Hepatic plasma clearance 0.013267 mL/sec/cm3 0.000000 10 2 S10-03
144 H Hematocrit 0.418000 0.000000 10 1 S10-04
145 ve Liver extracellular volume fraction 0.230000 mL/cm3 0.000000 10 1 S10-04
146 khe Hepatocellular uptake rate 0.034563 mL/sec/cm3 0.003415 10 1 S10-04
147 Th Hepatocellular mean transit time 221.220680 sec 23.197005 10 1 S10-04
148 Kbh Biliary tissue excretion rate 0.004520 mL/sec/cm3 0.000000 10 1 S10-04
149 Khe Hepatocellular tissue uptake rate 0.150275 mL/sec/cm3 0.000000 10 1 S10-04
150 kbh Biliary excretion rate 0.003481 mL/sec/cm3 0.000000 10 1 S10-04
151 E Liver extraction fraction 0.610850 0.000000 10 1 S10-04
152 Ktrans Hepatic plasma clearance 0.013450 mL/sec/cm3 0.000000 10 1 S10-04
153 H Hematocrit 0.418000 0.000000 10 2 S10-04
154 ve Liver extracellular volume fraction 0.230000 mL/cm3 0.000000 10 2 S10-04
155 khe Hepatocellular uptake rate 0.027510 mL/sec/cm3 0.001591 10 2 S10-04
156 Th Hepatocellular mean transit time 248.825391 sec 15.598687 10 2 S10-04
157 Kbh Biliary tissue excretion rate 0.004019 mL/sec/cm3 0.000000 10 2 S10-04
158 Khe Hepatocellular tissue uptake rate 0.119610 mL/sec/cm3 0.000000 10 2 S10-04
159 kbh Biliary excretion rate 0.003095 mL/sec/cm3 0.000000 10 2 S10-04
160 E Liver extraction fraction 0.555435 0.000000 10 2 S10-04
161 Ktrans Hepatic plasma clearance 0.012230 mL/sec/cm3 0.000000 10 2 S10-04
162 H Hematocrit 0.418000 0.000000 10 1 S10-05
163 ve Liver extracellular volume fraction 0.230000 mL/cm3 0.000000 10 1 S10-05
164 khe Hepatocellular uptake rate 0.032724 mL/sec/cm3 0.002464 10 1 S10-05
165 Th Hepatocellular mean transit time 203.321189 sec 16.233566 10 1 S10-05
166 Kbh Biliary tissue excretion rate 0.004918 mL/sec/cm3 0.000000 10 1 S10-05
167 Khe Hepatocellular tissue uptake rate 0.142280 mL/sec/cm3 0.000000 10 1 S10-05
168 kbh Biliary excretion rate 0.003787 mL/sec/cm3 0.000000 10 1 S10-05
169 E Liver extraction fraction 0.597778 0.000000 10 1 S10-05
170 Ktrans Hepatic plasma clearance 0.013162 mL/sec/cm3 0.000000 10 1 S10-05
171 H Hematocrit 0.418000 0.000000 10 2 S10-05
172 ve Liver extracellular volume fraction 0.230000 mL/cm3 0.000000 10 2 S10-05
173 khe Hepatocellular uptake rate 0.034150 mL/sec/cm3 0.002115 10 2 S10-05
174 Th Hepatocellular mean transit time 256.904592 sec 17.077545 10 2 S10-05
175 Kbh Biliary tissue excretion rate 0.003892 mL/sec/cm3 0.000000 10 2 S10-05
176 Khe Hepatocellular tissue uptake rate 0.148477 mL/sec/cm3 0.000000 10 2 S10-05
177 kbh Biliary excretion rate 0.002997 mL/sec/cm3 0.000000 10 2 S10-05
178 E Liver extraction fraction 0.607985 0.000000 10 2 S10-05
179 Ktrans Hepatic plasma clearance 0.013387 mL/sec/cm3 0.000000 10 2 S10-05
180 H Hematocrit 0.418000 0.000000 10 1 S10-06
181 ve Liver extracellular volume fraction 0.230000 mL/cm3 0.000000 10 1 S10-06
182 khe Hepatocellular uptake rate 0.039966 mL/sec/cm3 0.002838 10 1 S10-06
183 Th Hepatocellular mean transit time 225.378400 sec 16.843082 10 1 S10-06
184 Kbh Biliary tissue excretion rate 0.004437 mL/sec/cm3 0.000000 10 1 S10-06
185 Khe Hepatocellular tissue uptake rate 0.173767 mL/sec/cm3 0.000000 10 1 S10-06
186 kbh Biliary excretion rate 0.003416 mL/sec/cm3 0.000000 10 1 S10-06
187 E Liver extraction fraction 0.644771 0.000000 10 1 S10-06
188 Ktrans Hepatic plasma clearance 0.014197 mL/sec/cm3 0.000000 10 1 S10-06
189 H Hematocrit 0.418000 0.000000 10 2 S10-06
190 ve Liver extracellular volume fraction 0.230000 mL/cm3 0.000000 10 2 S10-06
191 khe Hepatocellular uptake rate 0.036884 mL/sec/cm3 0.002698 10 2 S10-06
192 Th Hepatocellular mean transit time 268.185300 sec 21.041762 10 2 S10-06
193 Kbh Biliary tissue excretion rate 0.003729 mL/sec/cm3 0.000000 10 2 S10-06
194 Khe Hepatocellular tissue uptake rate 0.160366 mL/sec/cm3 0.000000 10 2 S10-06
195 kbh Biliary excretion rate 0.002871 mL/sec/cm3 0.000000 10 2 S10-06
196 E Liver extraction fraction 0.626183 0.000000 10 2 S10-06
197 Ktrans Hepatic plasma clearance 0.013788 mL/sec/cm3 0.000000 10 2 S10-06
198 H Hematocrit 0.418000 0.000000 9 1 S09-01
199 ve Liver extracellular volume fraction 0.230000 mL/cm3 0.000000 9 1 S09-01
200 khe Hepatocellular uptake rate 0.020030 mL/sec/cm3 0.000709 9 1 S09-01
201 Th Hepatocellular mean transit time 373.947283 sec 15.530816 9 1 S09-01
202 Kbh Biliary tissue excretion rate 0.002674 mL/sec/cm3 0.000000 9 1 S09-01
203 Khe Hepatocellular tissue uptake rate 0.087087 mL/sec/cm3 0.000000 9 1 S09-01
204 kbh Biliary excretion rate 0.002059 mL/sec/cm3 0.000000 9 1 S09-01
205 E Liver extraction fraction 0.476350 0.000000 9 1 S09-01
206 Ktrans Hepatic plasma clearance 0.010489 mL/sec/cm3 0.000000 9 1 S09-01
207 H Hematocrit 0.418000 0.000000 9 2 S09-01
208 ve Liver extracellular volume fraction 0.230000 mL/cm3 0.000000 9 2 S09-01
209 khe Hepatocellular uptake rate 0.019136 mL/sec/cm3 0.000890 9 2 S09-01
210 Th Hepatocellular mean transit time 331.575221 sec 17.678724 9 2 S09-01
211 Kbh Biliary tissue excretion rate 0.003016 mL/sec/cm3 0.000000 9 2 S09-01
212 Khe Hepatocellular tissue uptake rate 0.083200 mL/sec/cm3 0.000000 9 2 S09-01
213 kbh Biliary excretion rate 0.002322 mL/sec/cm3 0.000000 9 2 S09-01
214 E Liver extraction fraction 0.464975 0.000000 9 2 S09-01
215 Ktrans Hepatic plasma clearance 0.010238 mL/sec/cm3 0.000000 9 2 S09-01
216 H Hematocrit 0.418000 0.000000 9 1 S09-02
217 ve Liver extracellular volume fraction 0.230000 mL/cm3 0.000000 9 1 S09-02
218 khe Hepatocellular uptake rate 0.017119 mL/sec/cm3 0.001287 9 1 S09-02
219 Th Hepatocellular mean transit time 231.522778 sec 19.151147 9 1 S09-02
220 Kbh Biliary tissue excretion rate 0.004319 mL/sec/cm3 0.000000 9 1 S09-02
221 Khe Hepatocellular tissue uptake rate 0.074433 mL/sec/cm3 0.000000 9 1 S09-02
222 kbh Biliary excretion rate 0.003326 mL/sec/cm3 0.000000 9 1 S09-02
223 E Liver extraction fraction 0.437408 0.000000 9 1 S09-02
224 Ktrans Hepatic plasma clearance 0.009631 mL/sec/cm3 0.000000 9 1 S09-02
225 H Hematocrit 0.418000 0.000000 9 2 S09-02
226 ve Liver extracellular volume fraction 0.230000 mL/cm3 0.000000 9 2 S09-02
227 khe Hepatocellular uptake rate 0.022700 mL/sec/cm3 0.001491 9 2 S09-02
228 Th Hepatocellular mean transit time 326.272113 sec 24.293174 9 2 S09-02
229 Kbh Biliary tissue excretion rate 0.003065 mL/sec/cm3 0.000000 9 2 S09-02
230 Khe Hepatocellular tissue uptake rate 0.098694 mL/sec/cm3 0.000000 9 2 S09-02
231 kbh Biliary excretion rate 0.002360 mL/sec/cm3 0.000000 9 2 S09-02
232 E Liver extraction fraction 0.507611 0.000000 9 2 S09-02
233 Ktrans Hepatic plasma clearance 0.011177 mL/sec/cm3 0.000000 9 2 S09-02
234 H Hematocrit 0.418000 0.000000 9 1 S09-03
235 ve Liver extracellular volume fraction 0.230000 mL/cm3 0.000000 9 1 S09-03
236 khe Hepatocellular uptake rate 0.028307 mL/sec/cm3 0.002243 9 1 S09-03
237 Th Hepatocellular mean transit time 297.434220 sec 26.028315 9 1 S09-03
238 Kbh Biliary tissue excretion rate 0.003362 mL/sec/cm3 0.000000 9 1 S09-03
239 Khe Hepatocellular tissue uptake rate 0.123073 mL/sec/cm3 0.000000 9 1 S09-03
240 kbh Biliary excretion rate 0.002589 mL/sec/cm3 0.000000 9 1 S09-03
241 E Liver extraction fraction 0.562470 0.000000 9 1 S09-03
242 Ktrans Hepatic plasma clearance 0.012385 mL/sec/cm3 0.000000 9 1 S09-03
243 H Hematocrit 0.418000 0.000000 9 2 S09-03
244 ve Liver extracellular volume fraction 0.230000 mL/cm3 0.000000 9 2 S09-03
245 khe Hepatocellular uptake rate 0.025216 mL/sec/cm3 0.001579 9 2 S09-03
246 Th Hepatocellular mean transit time 327.688375 sec 23.156375 9 2 S09-03
247 Kbh Biliary tissue excretion rate 0.003052 mL/sec/cm3 0.000000 9 2 S09-03
248 Khe Hepatocellular tissue uptake rate 0.109635 mL/sec/cm3 0.000000 9 2 S09-03
249 kbh Biliary excretion rate 0.002350 mL/sec/cm3 0.000000 9 2 S09-03
250 E Liver extraction fraction 0.533843 0.000000 9 2 S09-03
251 Ktrans Hepatic plasma clearance 0.011755 mL/sec/cm3 0.000000 9 2 S09-03
252 H Hematocrit 0.418000 0.000000 8 1 S08-01
253 ve Liver extracellular volume fraction 0.230000 mL/cm3 0.000000 8 1 S08-01
254 khe Hepatocellular uptake rate 0.029344 mL/sec/cm3 0.001970 8 1 S08-01
255 Th Hepatocellular mean transit time 408.262045 sec 31.838820 8 1 S08-01
256 Kbh Biliary tissue excretion rate 0.002449 mL/sec/cm3 0.000000 8 1 S08-01
257 Khe Hepatocellular tissue uptake rate 0.127585 mL/sec/cm3 0.000000 8 1 S08-01
258 kbh Biliary excretion rate 0.001886 mL/sec/cm3 0.000000 8 1 S08-01
259 E Liver extraction fraction 0.571310 0.000000 8 1 S08-01
260 Ktrans Hepatic plasma clearance 0.012580 mL/sec/cm3 0.000000 8 1 S08-01
261 H Hematocrit 0.418000 0.000000 8 2 S08-01
262 ve Liver extracellular volume fraction 0.230000 mL/cm3 0.000000 8 2 S08-01
263 khe Hepatocellular uptake rate 0.003034 mL/sec/cm3 0.000466 8 2 S08-01
264 Th Hepatocellular mean transit time 850.042766 sec 227.108547 8 2 S08-01
265 Kbh Biliary tissue excretion rate 0.001176 mL/sec/cm3 0.000000 8 2 S08-01
266 Khe Hepatocellular tissue uptake rate 0.013192 mL/sec/cm3 0.000000 8 2 S08-01
267 kbh Biliary excretion rate 0.000906 mL/sec/cm3 0.000000 8 2 S08-01
268 E Liver extraction fraction 0.121106 0.000000 8 2 S08-01
269 Ktrans Hepatic plasma clearance 0.002667 mL/sec/cm3 0.000000 8 2 S08-01
270 H Hematocrit 0.418000 0.000000 8 1 S08-02
271 ve Liver extracellular volume fraction 0.230000 mL/cm3 0.000000 8 1 S08-02
272 khe Hepatocellular uptake rate 0.027849 mL/sec/cm3 0.002515 8 1 S08-02
273 Th Hepatocellular mean transit time 269.048876 sec 26.131604 8 1 S08-02
274 Kbh Biliary tissue excretion rate 0.003717 mL/sec/cm3 0.000000 8 1 S08-02
275 Khe Hepatocellular tissue uptake rate 0.121082 mL/sec/cm3 0.000000 8 1 S08-02
276 kbh Biliary excretion rate 0.002862 mL/sec/cm3 0.000000 8 1 S08-02
277 E Liver extraction fraction 0.558453 0.000000 8 1 S08-02
278 Ktrans Hepatic plasma clearance 0.012297 mL/sec/cm3 0.000000 8 1 S08-02
279 H Hematocrit 0.418000 0.000000 8 2 S08-02
280 ve Liver extracellular volume fraction 0.230000 mL/cm3 0.000000 8 2 S08-02
281 khe Hepatocellular uptake rate 0.003093 mL/sec/cm3 0.000567 8 2 S08-02
282 Th Hepatocellular mean transit time 742.109715 sec 218.143697 8 2 S08-02
283 Kbh Biliary tissue excretion rate 0.001348 mL/sec/cm3 0.000000 8 2 S08-02
284 Khe Hepatocellular tissue uptake rate 0.013450 mL/sec/cm3 0.000000 8 2 S08-02
285 kbh Biliary excretion rate 0.001038 mL/sec/cm3 0.000000 8 2 S08-02
286 E Liver extraction fraction 0.123182 0.000000 8 2 S08-02
287 Ktrans Hepatic plasma clearance 0.002712 mL/sec/cm3 0.000000 8 2 S08-02
288 H Hematocrit 0.418000 0.000000 8 1 S08-03
289 ve Liver extracellular volume fraction 0.230000 mL/cm3 0.000000 8 1 S08-03
290 khe Hepatocellular uptake rate 0.019728 mL/sec/cm3 0.001371 8 1 S08-03
291 Th Hepatocellular mean transit time 383.872404 sec 31.160715 8 1 S08-03
292 Kbh Biliary tissue excretion rate 0.002605 mL/sec/cm3 0.000000 8 1 S08-03
293 Khe Hepatocellular tissue uptake rate 0.085774 mL/sec/cm3 0.000000 8 1 S08-03
294 kbh Biliary excretion rate 0.002006 mL/sec/cm3 0.000000 8 1 S08-03
295 E Liver extraction fraction 0.472562 0.000000 8 1 S08-03
296 Ktrans Hepatic plasma clearance 0.010405 mL/sec/cm3 0.000000 8 1 S08-03
297 H Hematocrit 0.418000 0.000000 8 2 S08-03
298 ve Liver extracellular volume fraction 0.230000 mL/cm3 0.000000 8 2 S08-03
299 khe Hepatocellular uptake rate 0.002214 mL/sec/cm3 0.000386 8 2 S08-03
300 Th Hepatocellular mean transit time 1076.771454 sec 381.975331 8 2 S08-03
301 Kbh Biliary tissue excretion rate 0.000929 mL/sec/cm3 0.000000 8 2 S08-03
302 Khe Hepatocellular tissue uptake rate 0.009627 mL/sec/cm3 0.000000 8 2 S08-03
303 kbh Biliary excretion rate 0.000715 mL/sec/cm3 0.000000 8 2 S08-03
304 E Liver extraction fraction 0.091372 0.000000 8 2 S08-03
305 Ktrans Hepatic plasma clearance 0.002012 mL/sec/cm3 0.000000 8 2 S08-03
306 H Hematocrit 0.418000 0.000000 8 1 S08-04
307 ve Liver extracellular volume fraction 0.230000 mL/cm3 0.000000 8 1 S08-04
308 khe Hepatocellular uptake rate 0.018832 mL/sec/cm3 0.001177 8 1 S08-04
309 Th Hepatocellular mean transit time 435.387822 sec 33.054295 8 1 S08-04
310 Kbh Biliary tissue excretion rate 0.002297 mL/sec/cm3 0.000000 8 1 S08-04
311 Khe Hepatocellular tissue uptake rate 0.081878 mL/sec/cm3 0.000000 8 1 S08-04
312 kbh Biliary excretion rate 0.001769 mL/sec/cm3 0.000000 8 1 S08-04
313 E Liver extraction fraction 0.460991 0.000000 8 1 S08-04
314 Ktrans Hepatic plasma clearance 0.010151 mL/sec/cm3 0.000000 8 1 S08-04
315 H Hematocrit 0.418000 0.000000 8 2 S08-04
316 ve Liver extracellular volume fraction 0.230000 mL/cm3 0.000000 8 2 S08-04
317 khe Hepatocellular uptake rate 0.002796 mL/sec/cm3 0.000413 8 2 S08-04
318 Th Hepatocellular mean transit time 759.109378 sec 182.021469 8 2 S08-04
319 Kbh Biliary tissue excretion rate 0.001317 mL/sec/cm3 0.000000 8 2 S08-04
320 Khe Hepatocellular tissue uptake rate 0.012158 mL/sec/cm3 0.000000 8 2 S08-04
321 kbh Biliary excretion rate 0.001014 mL/sec/cm3 0.000000 8 2 S08-04
322 E Liver extraction fraction 0.112685 0.000000 8 2 S08-04
323 Ktrans Hepatic plasma clearance 0.002481 mL/sec/cm3 0.000000 8 2 S08-04
324 H Hematocrit 0.418000 0.000000 8 1 S08-05
325 ve Liver extracellular volume fraction 0.230000 mL/cm3 0.000000 8 1 S08-05
326 khe Hepatocellular uptake rate 0.025961 mL/sec/cm3 0.002111 8 1 S08-05
327 Th Hepatocellular mean transit time 262.092578 sec 22.959490 8 1 S08-05
328 Kbh Biliary tissue excretion rate 0.003815 mL/sec/cm3 0.000000 8 1 S08-05
329 Khe Hepatocellular tissue uptake rate 0.112874 mL/sec/cm3 0.000000 8 1 S08-05
330 kbh Biliary excretion rate 0.002938 mL/sec/cm3 0.000000 8 1 S08-05
331 E Liver extraction fraction 0.541079 0.000000 8 1 S08-05
332 Ktrans Hepatic plasma clearance 0.011914 mL/sec/cm3 0.000000 8 1 S08-05
333 H Hematocrit 0.418000 0.000000 8 2 S08-05
334 ve Liver extracellular volume fraction 0.230000 mL/cm3 0.000000 8 2 S08-05
335 khe Hepatocellular uptake rate 0.002245 mL/sec/cm3 0.000343 8 2 S08-05
336 Th Hepatocellular mean transit time 958.806102 sec 275.583681 8 2 S08-05
337 Kbh Biliary tissue excretion rate 0.001043 mL/sec/cm3 0.000000 8 2 S08-05
338 Khe Hepatocellular tissue uptake rate 0.009760 mL/sec/cm3 0.000000 8 2 S08-05
339 kbh Biliary excretion rate 0.000803 mL/sec/cm3 0.000000 8 2 S08-05
340 E Liver extraction fraction 0.092514 0.000000 8 2 S08-05
341 Ktrans Hepatic plasma clearance 0.002037 mL/sec/cm3 0.000000 8 2 S08-05
342 H Hematocrit 0.418000 0.000000 8 1 S08-06
343 ve Liver extracellular volume fraction 0.230000 mL/cm3 0.000000 8 1 S08-06
344 khe Hepatocellular uptake rate 0.025441 mL/sec/cm3 0.002053 8 1 S08-06
345 Th Hepatocellular mean transit time 295.237391 sec 26.068654 8 1 S08-06
346 Kbh Biliary tissue excretion rate 0.003387 mL/sec/cm3 0.000000 8 1 S08-06
347 Khe Hepatocellular tissue uptake rate 0.110613 mL/sec/cm3 0.000000 8 1 S08-06
348 kbh Biliary excretion rate 0.002608 mL/sec/cm3 0.000000 8 1 S08-06
349 E Liver extraction fraction 0.536050 0.000000 8 1 S08-06
350 Ktrans Hepatic plasma clearance 0.011803 mL/sec/cm3 0.000000 8 1 S08-06
351 H Hematocrit 0.418000 0.000000 8 2 S08-06
352 ve Liver extracellular volume fraction 0.230000 mL/cm3 0.000000 8 2 S08-06
353 khe Hepatocellular uptake rate 0.001989 mL/sec/cm3 0.000369 8 2 S08-06
354 Th Hepatocellular mean transit time 1046.481399 sec 387.308456 8 2 S08-06
355 Kbh Biliary tissue excretion rate 0.000956 mL/sec/cm3 0.000000 8 2 S08-06
356 Khe Hepatocellular tissue uptake rate 0.008648 mL/sec/cm3 0.000000 8 2 S08-06
357 kbh Biliary excretion rate 0.000736 mL/sec/cm3 0.000000 8 2 S08-06
358 E Liver extraction fraction 0.082846 0.000000 8 2 S08-06
359 Ktrans Hepatic plasma clearance 0.001824 mL/sec/cm3 0.000000 8 2 S08-06
360 H Hematocrit 0.418000 0.000000 7 1 S07-02
361 ve Liver extracellular volume fraction 0.230000 mL/cm3 0.000000 7 1 S07-02
362 khe Hepatocellular uptake rate 0.022070 mL/sec/cm3 0.002018 7 1 S07-02
363 Th Hepatocellular mean transit time 293.503375 sec 29.624750 7 1 S07-02
364 Kbh Biliary tissue excretion rate 0.003407 mL/sec/cm3 0.000000 7 1 S07-02
365 Khe Hepatocellular tissue uptake rate 0.095958 mL/sec/cm3 0.000000 7 1 S07-02
366 kbh Biliary excretion rate 0.002623 mL/sec/cm3 0.000000 7 1 S07-02
367 E Liver extraction fraction 0.500582 0.000000 7 1 S07-02
368 Ktrans Hepatic plasma clearance 0.011022 mL/sec/cm3 0.000000 7 1 S07-02
369 H Hematocrit 0.418000 0.000000 7 2 S07-02
370 ve Liver extracellular volume fraction 0.230000 mL/cm3 0.000000 7 2 S07-02
371 khe Hepatocellular uptake rate 0.012012 mL/sec/cm3 0.001000 7 2 S07-02
372 Th Hepatocellular mean transit time 260.758709 sec 24.245170 7 2 S07-02
373 Kbh Biliary tissue excretion rate 0.003835 mL/sec/cm3 0.000000 7 2 S07-02
374 Khe Hepatocellular tissue uptake rate 0.052225 mL/sec/cm3 0.000000 7 2 S07-02
375 kbh Biliary excretion rate 0.002953 mL/sec/cm3 0.000000 7 2 S07-02
376 E Liver extraction fraction 0.352967 0.000000 7 2 S07-02
377 Ktrans Hepatic plasma clearance 0.007772 mL/sec/cm3 0.000000 7 2 S07-02
378 H Hematocrit 0.418000 0.000000 7 1 S07-03
379 ve Liver extracellular volume fraction 0.230000 mL/cm3 0.000000 7 1 S07-03
380 khe Hepatocellular uptake rate 0.020564 mL/sec/cm3 0.002026 7 1 S07-03
381 Th Hepatocellular mean transit time 282.354635 sec 30.659355 7 1 S07-03
382 Kbh Biliary tissue excretion rate 0.003542 mL/sec/cm3 0.000000 7 1 S07-03
383 Khe Hepatocellular tissue uptake rate 0.089409 mL/sec/cm3 0.000000 7 1 S07-03
384 kbh Biliary excretion rate 0.002727 mL/sec/cm3 0.000000 7 1 S07-03
385 E Liver extraction fraction 0.482917 0.000000 7 1 S07-03
386 Ktrans Hepatic plasma clearance 0.010633 mL/sec/cm3 0.000000 7 1 S07-03
387 H Hematocrit 0.418000 0.000000 7 2 S07-03
388 ve Liver extracellular volume fraction 0.230000 mL/cm3 0.000000 7 2 S07-03
389 khe Hepatocellular uptake rate 0.014715 mL/sec/cm3 0.001503 7 2 S07-03
390 Th Hepatocellular mean transit time 263.644766 sec 29.904439 7 2 S07-03
391 Kbh Biliary tissue excretion rate 0.003793 mL/sec/cm3 0.000000 7 2 S07-03
392 Khe Hepatocellular tissue uptake rate 0.063980 mL/sec/cm3 0.000000 7 2 S07-03
393 kbh Biliary excretion rate 0.002921 mL/sec/cm3 0.000000 7 2 S07-03
394 E Liver extraction fraction 0.400588 0.000000 7 2 S07-03
395 Ktrans Hepatic plasma clearance 0.008821 mL/sec/cm3 0.000000 7 2 S07-03
396 H Hematocrit 0.418000 0.000000 7 1 S07-04
397 ve Liver extracellular volume fraction 0.230000 mL/cm3 0.000000 7 1 S07-04
398 khe Hepatocellular uptake rate 0.013127 mL/sec/cm3 0.000953 7 1 S07-04
399 Th Hepatocellular mean transit time 298.416370 sec 24.534799 7 1 S07-04
400 Kbh Biliary tissue excretion rate 0.003351 mL/sec/cm3 0.000000 7 1 S07-04
401 Khe Hepatocellular tissue uptake rate 0.057074 mL/sec/cm3 0.000000 7 1 S07-04
402 kbh Biliary excretion rate 0.002580 mL/sec/cm3 0.000000 7 1 S07-04
403 E Liver extraction fraction 0.373498 0.000000 7 1 S07-04
404 Ktrans Hepatic plasma clearance 0.008224 mL/sec/cm3 0.000000 7 1 S07-04
405 H Hematocrit 0.418000 0.000000 7 2 S07-04
406 ve Liver extracellular volume fraction 0.230000 mL/cm3 0.000000 7 2 S07-04
407 khe Hepatocellular uptake rate 0.005471 mL/sec/cm3 0.000503 7 2 S07-04
408 Th Hepatocellular mean transit time 360.852747 sec 39.769304 7 2 S07-04
409 Kbh Biliary tissue excretion rate 0.002771 mL/sec/cm3 0.000000 7 2 S07-04
410 Khe Hepatocellular tissue uptake rate 0.023788 mL/sec/cm3 0.000000 7 2 S07-04
411 kbh Biliary excretion rate 0.002134 mL/sec/cm3 0.000000 7 2 S07-04
412 E Liver extraction fraction 0.199027 0.000000 7 2 S07-04
413 Ktrans Hepatic plasma clearance 0.004382 mL/sec/cm3 0.000000 7 2 S07-04
414 H Hematocrit 0.418000 0.000000 7 1 S07-05
415 ve Liver extracellular volume fraction 0.230000 mL/cm3 0.000000 7 1 S07-05
416 khe Hepatocellular uptake rate 0.020795 mL/sec/cm3 0.002349 7 1 S07-05
417 Th Hepatocellular mean transit time 217.745080 sec 26.492837 7 1 S07-05
418 Kbh Biliary tissue excretion rate 0.004593 mL/sec/cm3 0.000000 7 1 S07-05
419 Khe Hepatocellular tissue uptake rate 0.090411 mL/sec/cm3 0.000000 7 1 S07-05
420 kbh Biliary excretion rate 0.003536 mL/sec/cm3 0.000000 7 1 S07-05
421 E Liver extraction fraction 0.485700 0.000000 7 1 S07-05
422 Ktrans Hepatic plasma clearance 0.010695 mL/sec/cm3 0.000000 7 1 S07-05
423 H Hematocrit 0.418000 0.000000 7 2 S07-05
424 ve Liver extracellular volume fraction 0.230000 mL/cm3 0.000000 7 2 S07-05
425 khe Hepatocellular uptake rate 0.005198 mL/sec/cm3 0.000558 7 2 S07-05
426 Th Hepatocellular mean transit time 411.657352 sec 54.774945 7 2 S07-05
427 Kbh Biliary tissue excretion rate 0.002429 mL/sec/cm3 0.000000 7 2 S07-05
428 Khe Hepatocellular tissue uptake rate 0.022600 mL/sec/cm3 0.000000 7 2 S07-05
429 kbh Biliary excretion rate 0.001870 mL/sec/cm3 0.000000 7 2 S07-05
430 E Liver extraction fraction 0.190986 0.000000 7 2 S07-05
431 Ktrans Hepatic plasma clearance 0.004205 mL/sec/cm3 0.000000 7 2 S07-05
432 H Hematocrit 0.418000 0.000000 7 1 S07-06
433 ve Liver extracellular volume fraction 0.230000 mL/cm3 0.000000 7 1 S07-06
434 khe Hepatocellular uptake rate 0.022667 mL/sec/cm3 0.002503 7 1 S07-06
435 Th Hepatocellular mean transit time 257.860271 sec 30.914503 7 1 S07-06
436 Kbh Biliary tissue excretion rate 0.003878 mL/sec/cm3 0.000000 7 1 S07-06
437 Khe Hepatocellular tissue uptake rate 0.098553 mL/sec/cm3 0.000000 7 1 S07-06
438 kbh Biliary excretion rate 0.002986 mL/sec/cm3 0.000000 7 1 S07-06
439 E Liver extraction fraction 0.507254 0.000000 7 1 S07-06
440 Ktrans Hepatic plasma clearance 0.011169 mL/sec/cm3 0.000000 7 1 S07-06
441 H Hematocrit 0.418000 0.000000 7 2 S07-06
442 ve Liver extracellular volume fraction 0.230000 mL/cm3 0.000000 7 2 S07-06
443 khe Hepatocellular uptake rate 0.016662 mL/sec/cm3 0.001340 7 2 S07-06
444 Th Hepatocellular mean transit time 279.900091 sec 25.041638 7 2 S07-06
445 Kbh Biliary tissue excretion rate 0.003573 mL/sec/cm3 0.000000 7 2 S07-06
446 Khe Hepatocellular tissue uptake rate 0.072444 mL/sec/cm3 0.000000 7 2 S07-06
447 kbh Biliary excretion rate 0.002751 mL/sec/cm3 0.000000 7 2 S07-06
448 E Liver extraction fraction 0.430756 0.000000 7 2 S07-06
449 Ktrans Hepatic plasma clearance 0.009485 mL/sec/cm3 0.000000 7 2 S07-06
450 H Hematocrit 0.418000 0.000000 6 1 S06-02
451 ve Liver extracellular volume fraction 0.230000 mL/cm3 0.000000 6 1 S06-02
452 khe Hepatocellular uptake rate 0.029692 mL/sec/cm3 0.001751 6 1 S06-02
453 Th Hepatocellular mean transit time 210.523275 sec 13.254362 6 1 S06-02
454 Kbh Biliary tissue excretion rate 0.004750 mL/sec/cm3 0.000000 6 1 S06-02
455 Khe Hepatocellular tissue uptake rate 0.129094 mL/sec/cm3 0.000000 6 1 S06-02
456 kbh Biliary excretion rate 0.003658 mL/sec/cm3 0.000000 6 1 S06-02
457 E Liver extraction fraction 0.574188 0.000000 6 1 S06-02
458 Ktrans Hepatic plasma clearance 0.012643 mL/sec/cm3 0.000000 6 1 S06-02
459 H Hematocrit 0.418000 0.000000 6 2 S06-02
460 ve Liver extracellular volume fraction 0.230000 mL/cm3 0.000000 6 2 S06-02
461 khe Hepatocellular uptake rate 0.028013 mL/sec/cm3 0.001196 6 2 S06-02
462 Th Hepatocellular mean transit time 251.251402 sec 11.632323 6 2 S06-02
463 Kbh Biliary tissue excretion rate 0.003980 mL/sec/cm3 0.000000 6 2 S06-02
464 Khe Hepatocellular tissue uptake rate 0.121795 mL/sec/cm3 0.000000 6 2 S06-02
465 kbh Biliary excretion rate 0.003065 mL/sec/cm3 0.000000 6 2 S06-02
466 E Liver extraction fraction 0.559901 0.000000 6 2 S06-02
467 Ktrans Hepatic plasma clearance 0.012328 mL/sec/cm3 0.000000 6 2 S06-02
468 H Hematocrit 0.418000 0.000000 6 1 S06-03
469 ve Liver extracellular volume fraction 0.230000 mL/cm3 0.000000 6 1 S06-03
470 khe Hepatocellular uptake rate 0.025392 mL/sec/cm3 0.002823 6 1 S06-03
471 Th Hepatocellular mean transit time 162.886138 sec 19.312284 6 1 S06-03
472 Kbh Biliary tissue excretion rate 0.006139 mL/sec/cm3 0.000000 6 1 S06-03
473 Khe Hepatocellular tissue uptake rate 0.110399 mL/sec/cm3 0.000000 6 1 S06-03
474 kbh Biliary excretion rate 0.004727 mL/sec/cm3 0.000000 6 1 S06-03
475 E Liver extraction fraction 0.535569 0.000000 6 1 S06-03
476 Ktrans Hepatic plasma clearance 0.011793 mL/sec/cm3 0.000000 6 1 S06-03
477 H Hematocrit 0.418000 0.000000 6 2 S06-03
478 ve Liver extracellular volume fraction 0.230000 mL/cm3 0.000000 6 2 S06-03
479 khe Hepatocellular uptake rate 0.025035 mL/sec/cm3 0.001321 6 2 S06-03
480 Th Hepatocellular mean transit time 219.717326 sec 12.519368 6 2 S06-03
481 Kbh Biliary tissue excretion rate 0.004551 mL/sec/cm3 0.000000 6 2 S06-03
482 Khe Hepatocellular tissue uptake rate 0.108848 mL/sec/cm3 0.000000 6 2 S06-03
483 kbh Biliary excretion rate 0.003505 mL/sec/cm3 0.000000 6 2 S06-03
484 E Liver extraction fraction 0.532048 0.000000 6 2 S06-03
485 Ktrans Hepatic plasma clearance 0.011715 mL/sec/cm3 0.000000 6 2 S06-03
486 H Hematocrit 0.418000 0.000000 6 1 S06-04
487 ve Liver extracellular volume fraction 0.230000 mL/cm3 0.000000 6 1 S06-04
488 khe Hepatocellular uptake rate 0.020645 mL/sec/cm3 0.001435 6 1 S06-04
489 Th Hepatocellular mean transit time 173.413608 sec 12.984491 6 1 S06-04
490 Kbh Biliary tissue excretion rate 0.005767 mL/sec/cm3 0.000000 6 1 S06-04
491 Khe Hepatocellular tissue uptake rate 0.089759 mL/sec/cm3 0.000000 6 1 S06-04
492 kbh Biliary excretion rate 0.004440 mL/sec/cm3 0.000000 6 1 S06-04
493 E Liver extraction fraction 0.483893 0.000000 6 1 S06-04
494 Ktrans Hepatic plasma clearance 0.010655 mL/sec/cm3 0.000000 6 1 S06-04
495 H Hematocrit 0.418000 0.000000 6 2 S06-04
496 ve Liver extracellular volume fraction 0.230000 mL/cm3 0.000000 6 2 S06-04
497 khe Hepatocellular uptake rate 0.016584 mL/sec/cm3 0.001561 6 2 S06-04
498 Th Hepatocellular mean transit time 202.547253 sec 20.828141 6 2 S06-04
499 Kbh Biliary tissue excretion rate 0.004937 mL/sec/cm3 0.000000 6 2 S06-04
500 Khe Hepatocellular tissue uptake rate 0.072105 mL/sec/cm3 0.000000 6 2 S06-04
501 kbh Biliary excretion rate 0.003802 mL/sec/cm3 0.000000 6 2 S06-04
502 E Liver extraction fraction 0.429607 0.000000 6 2 S06-04
503 Ktrans Hepatic plasma clearance 0.009460 mL/sec/cm3 0.000000 6 2 S06-04
504 H Hematocrit 0.418000 0.000000 6 1 S06-05
505 ve Liver extracellular volume fraction 0.230000 mL/cm3 0.000000 6 1 S06-05
506 khe Hepatocellular uptake rate 0.019787 mL/sec/cm3 0.001499 6 1 S06-05
507 Th Hepatocellular mean transit time 170.731411 sec 13.947304 6 1 S06-05
508 Kbh Biliary tissue excretion rate 0.005857 mL/sec/cm3 0.000000 6 1 S06-05
509 Khe Hepatocellular tissue uptake rate 0.086031 mL/sec/cm3 0.000000 6 1 S06-05
510 kbh Biliary excretion rate 0.004510 mL/sec/cm3 0.000000 6 1 S06-05
511 E Liver extraction fraction 0.473306 0.000000 6 1 S06-05
512 Ktrans Hepatic plasma clearance 0.010422 mL/sec/cm3 0.000000 6 1 S06-05
513 H Hematocrit 0.418000 0.000000 6 2 S06-05
514 ve Liver extracellular volume fraction 0.230000 mL/cm3 0.000000 6 2 S06-05
515 khe Hepatocellular uptake rate 0.020136 mL/sec/cm3 0.001051 6 2 S06-05
516 Th Hepatocellular mean transit time 241.444429 sec 13.829168 6 2 S06-05
517 Kbh Biliary tissue excretion rate 0.004142 mL/sec/cm3 0.000000 6 2 S06-05
518 Khe Hepatocellular tissue uptake rate 0.087547 mL/sec/cm3 0.000000 6 2 S06-05
519 kbh Biliary excretion rate 0.003189 mL/sec/cm3 0.000000 6 2 S06-05
520 E Liver extraction fraction 0.477662 0.000000 6 2 S06-05
521 Ktrans Hepatic plasma clearance 0.010518 mL/sec/cm3 0.000000 6 2 S06-05
522 H Hematocrit 0.418000 0.000000 6 1 S06-06
523 ve Liver extracellular volume fraction 0.230000 mL/cm3 0.000000 6 1 S06-06
524 khe Hepatocellular uptake rate 0.020815 mL/sec/cm3 0.001524 6 1 S06-06
525 Th Hepatocellular mean transit time 231.684464 sec 18.526224 6 1 S06-06
526 Kbh Biliary tissue excretion rate 0.004316 mL/sec/cm3 0.000000 6 1 S06-06
527 Khe Hepatocellular tissue uptake rate 0.090499 mL/sec/cm3 0.000000 6 1 S06-06
528 kbh Biliary excretion rate 0.003323 mL/sec/cm3 0.000000 6 1 S06-06
529 E Liver extraction fraction 0.485944 0.000000 6 1 S06-06
530 Ktrans Hepatic plasma clearance 0.010700 mL/sec/cm3 0.000000 6 1 S06-06
531 H Hematocrit 0.418000 0.000000 6 2 S06-06
532 ve Liver extracellular volume fraction 0.230000 mL/cm3 0.000000 6 2 S06-06
533 khe Hepatocellular uptake rate 0.023018 mL/sec/cm3 0.001236 6 2 S06-06
534 Th Hepatocellular mean transit time 234.548587 sec 13.712021 6 2 S06-06
535 Kbh Biliary tissue excretion rate 0.004264 mL/sec/cm3 0.000000 6 2 S06-06
536 Khe Hepatocellular tissue uptake rate 0.100077 mL/sec/cm3 0.000000 6 2 S06-06
537 kbh Biliary excretion rate 0.003283 mL/sec/cm3 0.000000 6 2 S06-06
538 E Liver extraction fraction 0.511089 0.000000 6 2 S06-06
539 Ktrans Hepatic plasma clearance 0.011254 mL/sec/cm3 0.000000 6 2 S06-06
540 H Hematocrit 0.418000 0.000000 12 1 S12-01
541 ve Liver extracellular volume fraction 0.230000 mL/cm3 0.000000 12 1 S12-01
542 khe Hepatocellular uptake rate 0.030000 mL/sec/cm3 0.001981 12 1 S12-01
543 Th Hepatocellular mean transit time 326.139621 sec 23.676019 12 1 S12-01
544 Kbh Biliary tissue excretion rate 0.003066 mL/sec/cm3 0.000000 12 1 S12-01
545 Khe Hepatocellular tissue uptake rate 0.130435 mL/sec/cm3 0.000000 12 1 S12-01
546 kbh Biliary excretion rate 0.002361 mL/sec/cm3 0.000000 12 1 S12-01
547 E Liver extraction fraction 0.576713 0.000000 12 1 S12-01
548 Ktrans Hepatic plasma clearance 0.012699 mL/sec/cm3 0.000000 12 1 S12-01
549 H Hematocrit 0.418000 0.000000 12 2 S12-01
550 ve Liver extracellular volume fraction 0.230000 mL/cm3 0.000000 12 2 S12-01
551 khe Hepatocellular uptake rate 0.015164 mL/sec/cm3 0.000936 12 2 S12-01
552 Th Hepatocellular mean transit time 457.120966 sec 35.138295 12 2 S12-01
553 Kbh Biliary tissue excretion rate 0.002188 mL/sec/cm3 0.000000 12 2 S12-01
554 Khe Hepatocellular tissue uptake rate 0.065932 mL/sec/cm3 0.000000 12 2 S12-01
555 kbh Biliary excretion rate 0.001684 mL/sec/cm3 0.000000 12 2 S12-01
556 E Liver extraction fraction 0.407827 0.000000 12 2 S12-01
557 Ktrans Hepatic plasma clearance 0.008980 mL/sec/cm3 0.000000 12 2 S12-01
558 H Hematocrit 0.418000 0.000000 12 1 S12-02
559 ve Liver extracellular volume fraction 0.230000 mL/cm3 0.000000 12 1 S12-02
560 khe Hepatocellular uptake rate 0.027448 mL/sec/cm3 0.001948 12 1 S12-02
561 Th Hepatocellular mean transit time 262.269019 sec 19.984344 12 1 S12-02
562 Kbh Biliary tissue excretion rate 0.003813 mL/sec/cm3 0.000000 12 1 S12-02
563 Khe Hepatocellular tissue uptake rate 0.119340 mL/sec/cm3 0.000000 12 1 S12-02
564 kbh Biliary excretion rate 0.002936 mL/sec/cm3 0.000000 12 1 S12-02
565 E Liver extraction fraction 0.554877 0.000000 12 1 S12-02
566 Ktrans Hepatic plasma clearance 0.012218 mL/sec/cm3 0.000000 12 1 S12-02
567 H Hematocrit 0.418000 0.000000 12 2 S12-02
568 ve Liver extracellular volume fraction 0.230000 mL/cm3 0.000000 12 2 S12-02
569 khe Hepatocellular uptake rate 0.012936 mL/sec/cm3 0.000524 12 2 S12-02
570 Th Hepatocellular mean transit time 490.460001 sec 25.525220 12 2 S12-02
571 Kbh Biliary tissue excretion rate 0.002039 mL/sec/cm3 0.000000 12 2 S12-02
572 Khe Hepatocellular tissue uptake rate 0.056244 mL/sec/cm3 0.000000 12 2 S12-02
573 kbh Biliary excretion rate 0.001570 mL/sec/cm3 0.000000 12 2 S12-02
574 E Liver extraction fraction 0.370079 0.000000 12 2 S12-02
575 Ktrans Hepatic plasma clearance 0.008149 mL/sec/cm3 0.000000 12 2 S12-02
576 H Hematocrit 0.418000 0.000000 12 1 S12-03
577 ve Liver extracellular volume fraction 0.230000 mL/cm3 0.000000 12 1 S12-03
578 khe Hepatocellular uptake rate 0.030764 mL/sec/cm3 0.002113 12 1 S12-03
579 Th Hepatocellular mean transit time 261.478684 sec 19.132158 12 1 S12-03
580 Kbh Biliary tissue excretion rate 0.003824 mL/sec/cm3 0.000000 12 1 S12-03
581 Khe Hepatocellular tissue uptake rate 0.133755 mL/sec/cm3 0.000000 12 1 S12-03
582 kbh Biliary excretion rate 0.002945 mL/sec/cm3 0.000000 12 1 S12-03
583 E Liver extraction fraction 0.582837 0.000000 12 1 S12-03
584 Ktrans Hepatic plasma clearance 0.012833 mL/sec/cm3 0.000000 12 1 S12-03
585 H Hematocrit 0.418000 0.000000 12 2 S12-03
586 ve Liver extracellular volume fraction 0.230000 mL/cm3 0.000000 12 2 S12-03
587 khe Hepatocellular uptake rate 0.013389 mL/sec/cm3 0.000746 12 2 S12-03
588 Th Hepatocellular mean transit time 445.116547 sec 30.753409 12 2 S12-03
589 Kbh Biliary tissue excretion rate 0.002247 mL/sec/cm3 0.000000 12 2 S12-03
590 Khe Hepatocellular tissue uptake rate 0.058213 mL/sec/cm3 0.000000 12 2 S12-03
591 kbh Biliary excretion rate 0.001730 mL/sec/cm3 0.000000 12 2 S12-03
592 E Liver extraction fraction 0.378135 0.000000 12 2 S12-03
593 Ktrans Hepatic plasma clearance 0.008326 mL/sec/cm3 0.000000 12 2 S12-03
594 H Hematocrit 0.418000 0.000000 12 1 S12-04
595 ve Liver extracellular volume fraction 0.230000 mL/cm3 0.000000 12 1 S12-04
596 khe Hepatocellular uptake rate 0.028471 mL/sec/cm3 0.001859 12 1 S12-04
597 Th Hepatocellular mean transit time 269.447999 sec 18.903053 12 1 S12-04
598 Kbh Biliary tissue excretion rate 0.003711 mL/sec/cm3 0.000000 12 1 S12-04
599 Khe Hepatocellular tissue uptake rate 0.123788 mL/sec/cm3 0.000000 12 1 S12-04
600 kbh Biliary excretion rate 0.002858 mL/sec/cm3 0.000000 12 1 S12-04
601 E Liver extraction fraction 0.563896 0.000000 12 1 S12-04
602 Ktrans Hepatic plasma clearance 0.012416 mL/sec/cm3 0.000000 12 1 S12-04
603 H Hematocrit 0.418000 0.000000 12 2 S12-04
604 ve Liver extracellular volume fraction 0.230000 mL/cm3 0.000000 12 2 S12-04
605 khe Hepatocellular uptake rate 0.010416 mL/sec/cm3 0.000509 12 2 S12-04
606 Th Hepatocellular mean transit time 587.827030 sec 40.133174 12 2 S12-04
607 Kbh Biliary tissue excretion rate 0.001701 mL/sec/cm3 0.000000 12 2 S12-04
608 Khe Hepatocellular tissue uptake rate 0.045289 mL/sec/cm3 0.000000 12 2 S12-04
609 kbh Biliary excretion rate 0.001310 mL/sec/cm3 0.000000 12 2 S12-04
610 E Liver extraction fraction 0.321143 0.000000 12 2 S12-04
611 Ktrans Hepatic plasma clearance 0.007071 mL/sec/cm3 0.000000 12 2 S12-04
Plot individual results#
Now lets visualise the main results from the study by plotting the drug
effect for all rats, and for both biomarkers: uptake rate khe and
excretion rate kbh:
# Set up the figure
clr = ['tab:blue', 'tab:orange', 'tab:green', 'tab:red', 'tab:purple',
'tab:brown']
fs = 10
fig, ax = plt.subplots(2, 6, figsize=(6*1.5, 8))
fig.subplots_adjust(wspace=0.2, hspace=0.1)
# Loop over all studies
studies = [5,10,8,7,6,12]
drugs = ['Asunaprevir','Bosentan','Cyclosporine','Ketoconazole',
'Pioglitazone','Rifampicin']
for i, s in enumerate(studies):
# Set up subfigures for the study
ax[0,i].set_title(drugs[i], fontsize=fs, pad=10)
ax[0,i].set_ylim(0, 300)
ax[0,i].set_xticklabels([])
ax[1,i].set_ylim(0, 30)
ax[1,i].set_xticklabels([])
if i==0:
ax[0,i].set_ylabel('khe (mL/min/100mL)', fontsize=fs)
ax[0,i].tick_params(axis='y', labelsize=fs)
ax[1,i].set_ylabel('kbh (mL/min/100mL)', fontsize=fs)
ax[1,i].tick_params(axis='y', labelsize=fs)
else:
ax[0,i].set_yticklabels([])
ax[1,i].set_yticklabels([])
# Pivot data for both visits of the study for easy access:
study = results[results.study==s]
v1 = pd.pivot_table(study[study.visit==1], values='value',
columns='parameter', index='subject')
v2 = pd.pivot_table(study[study.visit==2], values='value',
columns='parameter', index='subject')
# Plot the rate constants in units of mL/min/100mL
for s in v1.index:
x = [1]
khe = [6000*v1.at[s,'khe']]
kbh = [6000*v1.at[s,'kbh']]
if s in v2.index:
x += [2]
khe += [6000*v2.at[s,'khe']]
kbh += [6000*v2.at[s,'kbh']]
color = clr[int(s[-2:])-1]
ax[0,i].plot(x, khe, '-', label=s, marker='o', markersize=6,
color=color)
ax[1,i].plot(x, kbh, '-', label=s, marker='o', markersize=6,
color=color)
plt.show()
Plot effect sizes#
Now lets calculate the effect sizes (relative change) for each drug, along with 95% confidence interval, and show these in a plot. Results are presented in red if inhibition is more than 20% (i.e. upper value of the 95% CI is less than -20%), in orange if inhbition is less than 20% (i.e. upper value of the 95% CI is less than 0%), and in green if no inhibition was detected with 95% confidence (0% in the 95% CI):
# Set up figure
fig, (ax0, ax1) = plt.subplots(1, 2, figsize=(6, 5))
fig.subplots_adjust(left=0.3, right=0.7, wspace=0.25)
ax0.set_title('khe effect (%)', fontsize=fs, pad=10)
ax1.set_title('kbh effect (%)', fontsize=fs, pad=10)
ax0.set_xlim(-100, 50)
ax1.set_xlim(-100, 50)
ax0.grid(which='major', axis='x', linestyle='-')
ax1.grid(which='major', axis='x', linestyle='-')
ax1.set_yticklabels([])
# Loop over all studies
for i, s in enumerate(studies):
# Pivot data for both visits of the study for easy access:
study = results[results.study==s]
v1 = pd.pivot_table(study[study.visit==1], values='value',
columns='parameter', index='subject')
v2 = pd.pivot_table(study[study.visit==2], values='value',
columns='parameter', index='subject')
# Calculate effect size for the drug in %
effect = 100*(v2-v1)/v1
# Get descriptive statistics
stats = effect.describe()
# Calculate mean effect sizes and 59% CI on the mean.
khe_eff = stats.at['mean','khe']
kbh_eff = stats.at['mean','kbh']
khe_eff_err = 1.96*stats.at['std','khe']/np.sqrt(stats.at['count','khe'])
kbh_eff_err = 1.96*stats.at['std','kbh']/np.sqrt(stats.at['count','kbh'])
# Plot mean effect size for khe along with 95% CI
# Choose color based on magnitude of effect
if khe_eff + khe_eff_err < -20:
clr = 'tab:red'
elif khe_eff + khe_eff_err < 0:
clr = 'tab:orange'
else:
clr = 'tab:green'
ax0.errorbar(khe_eff, drugs[i], xerr=khe_eff_err, fmt='o', color=clr)
# Plot mean effect size for kbh along with 95% CI
# Choose color based on magnitude of effect
if kbh_eff + kbh_eff_err < -20:
clr = 'tab:red'
elif kbh_eff + kbh_eff_err < 0:
clr = 'tab:orange'
else:
clr = 'tab:green'
ax1.errorbar(kbh_eff, drugs[i], xerr=kbh_eff_err, fmt='o', color=clr)
# Plot dummy values out of range to show a legend
ax1.errorbar(-200, drugs[0],
marker='o',
color='tab:red',
label='inhibition > 20%')
ax1.errorbar(-200, drugs[0],
marker='o',
color='tab:orange',
label='inhibition')
ax1.errorbar(-200, drugs[0],
marker='o',
color='tab:green',
label='no inhibition')
ax1.legend(loc='center left', bbox_to_anchor=(1, 0.5))
plt.show()
# Choose the last image as a thumbnail for the gallery
# sphinx_gallery_thumbnail_number = -1
Total running time of the script: (0 minutes 14.381 seconds)