Rodgers and Rowland Kp algorithm - Double accounting for protein binding contribution in tissue?

[a2mahara]

Hi there,
I am seeking clarification on the calculation of partition coefficients (Kps) in the interstitial and intracellular spaces in PK-Sim v11.

I created a simulation for a small molecule weak base in PK-Sim and exported it to MoBi to evaluate the calculation for Kp in the interstitial and intracellular spaces (Rodgers and Rowland's Kp algorithm).

I noticed that the equation for Kp (intracellular/plasma) includes binding to plasma proteins present in the interstitial space (i.e., the Ka_PR*T2PR_P_Albumin component):

Kp (intracellular/plasma):

According to the Rodgers and Rowland Kp algorithm (see image below), protein binding (PR) is only accounted for in the interstitial space (i.e., not intracellular space):

Additionally, the equation for Kp (interstitial/plasma) appears to incorporate protein binding (PR) via the component f_protein_int_to_pls * (1/fu - f_water_pls):

Kp (interstitial/plasma):

It seems that the Rodgers and Rowland algorithm (as implement in PK-Sim) accounts for protein binding in both the interstitial and intracellular spaces, which might lead to double-counting. I may be misunderstanding how this is implemented in PK-Sim, so I would appreciate any clarification.

Furthermore, for a strong base molecule under the Rodgers and Rowland Kp algorithm, there should be no need to account for protein binding in the interstitial space. However, the same Kp (interstitial/plasma) equation is used, implying that protein binding in the interstitial space is still included, even though the original algorithm does not account for it.

Can anyone provide clarity on these points?

Thank you!