Oleh :
Faika Hanum Salsabilah
NIM : 081711733005
D. TUGAS
Find the solution for linear equation sytem in following problem!
Pharmacokinetic modelling for “animal-on-chip”
A material balance is performed for naphthalene epoxide (NO)
generation, consumption, and transport in the µCCA device described
in Figure4.1; NO is an intermediate formed during the metabolism of
naphthalene.
Route of generation of naphthalene epoxide:
1. Conversion of naphthalene into its epoxide
Route of consumption of naphthalene epoxide:
1. Conversion of epoxide to naphthalene dihydrodiol
2. Binding to GSH to form epoxide-GSH conjugates
3. Rearrangement to naphthol
The material balancae diagram for naphthalene epoxide (MO) is
shown in Figure 4.1. Since we are dealing with a multicomponent
system, we use superscripts N,NO and NOH for naphthalene,
naphthalene epoxide, and naphthol, respectively, to differentiate
between the concentaration terms in various compartments.
A mass balance of NO is peformed over the two chambers – lung and
liver. This yields two linear equations is the unknowns C NO NO
lung and C liver .
NO
v max , p 450−lungC NO
v max ,GST C NO
C GSH
lung lung
GSH
- K NOH exp(l NOH T Plung) C NO NO
lung V lung- Q lung Clung = 0 ........
Kllung + K 2lung C lung
(1)
Liver comaprtment:
NO
v max , p 450−liver C NO
v max , GST C NO
C GSH
liver liver
GSH
- K NOH exp(l NOH T Pliver ) C NO NO
liver V liver - Q liver Cliver = 0 ........
Klliver + K 2liver C liver
(2)
NO balance assumptions
1. Binding of naphthalene epoxide to proteins is comparatively less
important and can be neglected.
2. The concentration of GSH in cells is constant. It is assumed that
GSH is resynthesized at the rate of consumption.
3. Production of the RS enantiomer of the epoxide (compared to SR
oxide) is dominant, and hence reaction parameters pertainin to RS
production only are used.
4. The total protein content inthe cells to which the metabolites blind
remains constant.
The parametric values and defimitions are provided below. The
modeling parameters correspond to naphthalene processing in mice.
Flowrates
Q lung: flowrate through lung compartment = 2 µl/min;
Q liver :flowrate through liver compartment = 5 µl/min;
Q ot : flowrate through other tissues compartment = 2 µl/min;
Compartment volumes
V lung = volume of lung compartment = 2 mmx2mmx20 µm=8x10l =
0.08 µl;
V liver = volume of liver compartment = 3.5 mmx4.6mmx20 µm=3.22 x
10-7l = 0.322 µl;
Reaction constants
(1) Naphthalene naphthalene epoxide
v max , p 450−lung: maximum reaction velocity for conversion of naphthalene
into naphthalene epoxide by cytochrome P450 monooxigenases in lung
cells = 8.75 µM/min;
v max , P 450−liver: maximum reaction velocity for conversion of naphthalene
into naphthalene epoxide by cytochrome P450 monooxigenases in liver
cells = 118 µM/min;
(2) Naphthalene naphthalene dyhidrodiol
v max , EH −lung: maximum reaction velocity for conversion of naphthalene
epoxide to dihydrodiol by epoxide hydrolase in the lung = 2.65
µM/min;
K m , EH −lung :Michaelis constant = 4.0 µM
v max , EH −lung: maximum reaction velocity for conversion of naphthalene
epoxide to dihydrodiol by epoxide hydrolase in the lung = 336
µM/min;
K m , EH −lung :Michaelis constant = 21 µM
(3) Naphthalene epoxide naphthol
K NOH : rate constant for rearrangement of epoxide to naphthol = 0.173
µM/ µM of NO /min;
l NOH : constant that relate naphthol formation rate to total pprotein
content = -20.2 ml/g protein
(4) Naphthalene epoxide epoxide-GSH conjugates
v max ,GST : maximum reaction velocity for binding of Naphthalene
epoxide to SH catalyzed by GST (glutathione S-transferase) = 2750 =
0.173 µM/min;
K 1lung: constant in epoxide-GSH binding rate = 310 000 µM2;
K 2lung: constant in epoxide-GSH binding rate = 35 µM;
K 1liver: constant in epoxide-GSH binding rate = 150 000 µM2;
K 2liver: constant in epoxide-GSH binding rate = 35 µM;
Protein concentrations
TPlung: total protein content in lung compartment = 92 mg/ml;
TPliver : total protein content in liver compartment =192 mg/ml;
C GSH
lung : GSH concentration in lung compartment = 1800 µM;
C GSH
liver : GSH concentration in liver compartment = 7500 µM;
2. Flowchart
3. Program
4. Analisis Program
F. KESIMPULAN
G. DAFTAR PUSTAKA