Plasma Protein Binding

Generally, only the unbound drug is available for diffusion or transport across cell membranes, and also for interaction with a pharmacological target. As a result, a degree of plasma protein binding of a drug influences not only on the drug’s action but also its disposition and efficacy. In PreADMET can predict percent drug bound in plasma protein as in vitro data on human.

Although there are some differences in the experimental values by compounds or their metabolisms, we can put into general categories like below.

Classification Plasma Protein Binding(%PPB)
Chemicals strongly bound more than 90%
Chemicals weakly bound less than 90%
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Blood Brain Barrier Penetration

Blood-Brain Barrier (BBB) penetration is represented as BB = [Brain]/[Blood], where [Brain] and [Blood] are the steady-state concentration of radiolabeled compounds in brain and peripheral blood. Predicting BBB penetration means predicting whether compounds pass across the blood-brain barrier. This is crucial in pharmaceutical sphere because CNS-active compounds must pass across it and CNS-inactive compounds mustn’t pass across it in order to avoid of CNS side effects. In PreADMET can predict in vivo data on rates for BBB penetration.

 

We can put into general categories like below, although there are some differences in the experimental values by compounds or their metabolisms.

[ Ajay,G.W. et al. J. Med. Chem. 1999, 42, 4942. ]

Classification BB (Cbrain/Cblood) logBB
CNS – Active compounds(+)  more than 1.0 more than 0
CNS – Inactive compounds(- )  less than 1.0 less than 0

 

There is another report for the classification. [ Lobell, M et al. J. Pharma. Sci. 2003, 92, 360. ]

Classification BB (Cbrain/Cblood) logBB
CNS – Active compounds(+) more than 0.40 more than -0.4
CNS – Inactive compounds(- ) less than 0.40 less than -0.4

 

The following is the actual classification that PreADMET uses. [ Ma X. et al. Acta Pharmacologica Sinica. 2005, 26, 500. ]

Classification BB (Cbrain/Cblood) logBB
High absorption to CNS more than 2.0 more than 0.3
Middle absorption to CNS 2.0 ~ 0.1 0.3 ~-1.0
Low absorption to CNS less than 0.1 less than -1.0
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Skin Permeability

In the pharmaceutical, cosmetic and agrochemical fields, it is important to predict the skin permeability rate for a crucial parameter for the transdermal delivery of drugs and for the risk assessment of all chemicals that come into contact with the skin either accidentally or by design. In PreADMET can predict in vitro data on human for skin permeability.

PreADMET predicts in vitro skin permeability and the result value is given as logKp. Kp (cm/hour) is defined as:

Kp= Km*D/h

 

where Km is distribution coefficient between stratum corneum and vehicle, and D is average diffusion coefficient (cm2/h), and h is thickness of skin (cm).

[ Singh,S. et al. Med. Res. Rev. 1993, 13, 569. ]

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Human Intestinal Absorption

Predicting human intestinal absorption of drugs is very important for identify potential drug candidate. In PreADMET can predict percent human intestinal absorption (%HIA). Human intestinal absorption data are the sum of bioavailability and absorption evaluated from ratio of excretion or cumulative excretion in urine , bile and feces.

[ Zhao,Y.H. et al. J. Pharm. Sci. 2001, 90, 749. ]

 

For prediction of HIA in PreADMET, chemical structures at pH 7.4 are applied, because HIA is measured by in vivo test. This is one of options of PreAMDET and user can choose for this option.

 

Although there are some differences in the experimental values by compounds or their metabolisms, we can put into general categories like below.

[ Yee,S. Pharm. Res. 1997, 14, 763. ]

 

Classification HIA (Human Intestinal Absorption)
Poorly absorbed compounds 0 ~ 20 %
Moderately absorbed compounds 20 ~ 70 %
Well absorbed compounds 70 ~ 100 %
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Caco2 cell permeability

Numerous in vitro methods have been used in the drug selection process for assessing the intestinal absorption of drug candidates. Among them, Caco-2 cell model and MDCK cell model has been recommended as a reliable in vitro model for the prediction of oral drug absorption.

[ Yamashita,S. et al. Eur. J. Pharm. 2000, 10, 195. ]

Caco-2 cells are derived from human colon adenocarcinoma and possess multiple drug transport pathways through the intestinal epithelium.

For prediction of Caco-2 cell permeability in PreADMET, chemical structures at pH 7.4 are applied, because Caco-2 cell permeability and MDCK cell permeability are measured at about pH 7.4. This is one of options of PreAMDET and user can choose for this option.

Although there are some differences in the experimental values by compounds or their metabolisms, we can put into general categories like below.

[ Yazdanian,M. Pharm. Res. 1998, 15(9), 1490. ]

Classification PCaco-2 (nm/sec)
Low permeability less than 4
Middle permeability 4 ~ 70
High permeability more than 70

[ (1) Yamashita,S. et al. Eur. J. Pharm. Sci. 2000, 10, 195., (2) Irvine,J.D. et al. J. Pharm. Sci. 1999, 88, 28. ]

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