Team:NTU-LIHPAO-Taiwan/Modeling/Conclusion

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Modeling Summary

Hypothesis

1. Total oral ingestion of 10⁹ L. casei on the first day.
2. The varying ratio (%) of bacteria number to total ingested number attached on the intestine against time were according to the mouse experiment.
3. Incorporate suicide mechanism: 4 days for bacteria survival.
4. TAT penetrates through villi by an uncharacterized pinocytosis/endocytosis related mechanism, which is also receptor-independent.
5. CPP-PYY complex production rate per L. casei : 10^-10 μg/min.
6. One-fourth of the products secreted from L. casei penetrate through the small intestine epithelial cells, without being digested by the intestine fluid.
7. Effective permeability of TAT-insulin conjugates from literature as reference for TAT-PYY complex : P_eff = 1.62×10^-5 (cm/s).
8. Mean total mucosal surface of the small intestine interior averages 32 m².
9. L. casei cell size range = 0.7-1.1 x 2.0-4.0 μm. One-tenth of the bacteria height multiplied the mucosa surface area for the donor chamber volume.
10. Fick’s Law of Binary Diffusion applied for CPP-PYY complex adsorption into bloodstream. Interstitial fluid diffusion coefficient of bovine serum albumin in tissues was taken for reference : D_AB = 5.8 x 10^-7 cm²/s.
11. The distance from epithelial cells to capillaries is 4 μm.
12. The diffusion is rapid enough to adsorb all the products in every minute.
13. All the calculation was based on reaching steady-state condition in the interval of every minute discretely.
14. Thrombin cleavage efficiency of Arg-Ser(R-S) site in CPP-PYY complex was referred to Arg-Thr(R-T) site in salmon calcitonin.
15. Nearly 100 % of the complexes would be cleaved during 30 minutes due to the fluid motion in circulation.
16. PYY concentration of 100 pg/ml has the power of appetite suppression without drug resistance.
17. Average total blood volume of 5 liter in human body.

Conclusion

Ideally, the optimal concentration of PYY is 0.1 μg/L for appetite suppression, giving little side effect. Here we performed the simulation with 10⁹ of total L. casei intake, and 10^-10 μg/min of CPP-PYY complex production rate per L. casei. The results is shown below.

[Fig.2-1] Final concentration of PYY (μg/L) in the blood vessel

By building the model for simulation step by step, we summarized the general formula with varies parameters to determine the dose response :

[Final concentration of PYY in the blood (μg/L)] = 11745 × [Total L. casei intake] × [Distribution ratio of L. casei] × [CPP-PYY complex production rate per L. casei (μg/min)]

This general formula is based on one-dose response, and continuous drug intake should be further modified by successive accumulation for determining the appetite suppression effect.

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