Skip to content
New issue

Have a question about this project? Sign up for a free GitHub account to open an issue and contact its maintainers and the community.

By clicking “Sign up for GitHub”, you agree to our terms of service and privacy statement. We’ll occasionally send you account related emails.

Already on GitHub? Sign in to your account

Strange values for partition coefficient #353

Open
MahmoudM3anl3ss opened this issue Jun 26, 2019 · 1 comment

Comments

Projects
None yet
3 participants
@MahmoudM3anl3ss
Copy link

commented Jun 26, 2019

Hello,

I'm new to using Pk-sim, just practicing with a basic PBPK model for clofazimine, which his highly lipophilic drug that accumulate mainly in adipose and fatty tissues mainly metabolized by liver (Cl : 0.26 l/h/kg)
given the published physicochemical characteristics of the drug,

Effective M.w: 429 (drug bank)
Fu : 0.01 (published study)
Logp : 7.66 (drug bank)
Water solubility : 0.233 mg/l (drug bank)
PKa is 8.6
When Pk-sim calculate (B/P ratio and Pc's), it gives me strange values, for example the B/p value of > 1 (2615.2) which I know is not correct, but if I log10 the value I get reasonable values for B/p ratio and Pc's.

What I'm missing or doing wrong ?

Thanks

Mahmoud

@StephanSchaller

This comment has been minimized.

Copy link
Member

commented Jun 26, 2019

Some initial thoughts:

In our experience, DrugBank LogP is often too high by some margin. LogD (@ph 7.4) or LogMA is more likely to be the right input for PK-Sim.
Also an fu of 0.01 is probably measured with high uncertainty. Increasing fu should also lower B:P.

What Partitioning Calculation Method did you use? For a highly lipophilic drug, I would recommend Rodgers and Rowland.

If you have data for B:P try first setting R&R as the calculation method, then decrease lipophilicity (Calculated LogP of ~7 often compare to LogD ~5) and maybe increase fu and see where you end up.

Hope this helps,
Stephan

Sign up for free to join this conversation on GitHub. Already have an account? Sign in to comment
You can’t perform that action at this time.