Subject: PB-PK Models

From: "Dr. Chris L. Waller" <[email-masked]>
Date: Fri, 7 Oct 1994 08:36:05 -0400 (EDT)

Dear CCLers:

At EPA, in the Environmental Toxicology Division, there is a group
dedicated to developing physiologically-based pharmacokinetic-models
(PB-PK) - thus the name of the Branch to which I belong. In short,
a PB-PK model attempts to model uptake, distribution, and elimintion
of chemicals (toxic or pharmacologic) by representing the body as
a series of compartments (lung, heart, liver, etc.) connected in 
parallel. Factors such as blood flow rates and tissue:blood partition
coefficients for given chemicals are included as terms in differential
equations which are solved simulataneously to model the system.

I know, you are asking, what does this have to do with Comp Chem?

Well, PB-PK models are typically single chmeical specific (i.e. a 
model works for chloroform and that's it!). When one wants to 
develop a model for carbontetrachloride, let's say, one goes to 
the lab and kills rats or whatever to determine the specific
partitioning and metabolic rate constants, etc. for this chemical.
Not very efficient.

I have been interested in using QSARs/QSPRs to allow the application
of a model developed for one chemical to be used for an entire
congerneric series of chemcials. So far, clogP can be used to 
"predict" fat:blood and liver:blood partitioning pretty well. I
have some other techniques which predict metabolic rate constants
and such.

So far, this is going OK. The major bottleneck seems to be with
the PB-PK modeling packages themselves. I am spoiled by the admittedly 
debatable "user friendliness" of most of the commercial molecular 
modeling packages. PB-PK modeling packages are not quite as 
friendly (at least the few that I have access to aren't). We have
ACSL (which runs on a PC or a VAX) and another package called
SimuSol (which runs on a VAX). My questions are (1) do any other 
molecular modelers have an interest in or know of anyone doing
work of the type described above (i.e. using molecular modeling
concepts to extend PB-PK models) and (2) what other PB-PK 
packages are commercially available/in-use in the pharmaceutical
company/academic environment?

The desired answer to this latter question is of course "Why yes
we have a package that runs on an Unix box with an X-windows interface
which is extremely friendly named ________ (fill in the blank)."

CW 

********************************************************************
*Chris L. Waller, Ph.D.                          PHONE 919-541-7976*
*Research Chemist                                FAX   919-541-5394*
[email-masked]                                          *
*Pharmacokinetics Branch (MD-74)                                   *
*ETD/HERL/USEPA                                                    *
*Research Triangle Park, NC 27711                                  *
*                                                                  *
*Disclaimer: Mention of trade names or products does not constitute*
*endorsement by the United States Environmental Protection Agency. *
********************************************************************