Free drug concentration at equilibrium in PK-Sim

[isperovani]

Hello everyone.

I am studying drug distribution and I have decided to use PK-Sim to evaluate how the free drug concentration behave in plasma interstitial and intracellular spaces and I came across a intriguing situation.

At this point, I am studying drug distribution only through passive diffusion, so the simulation I have setup does not account for metabolism nor transporter activity. The simulation I ran, I administered an IV infusion of 1 mg/kg erythromycin through the course of 1440 hours to give more than enough time for steady-state. The molecule I am evaluating is erythromycin, a strong base with a pKa of about 9. Because it is a base, it will be ionized in all tissue sub-compartments (plasma (pH = 7.4), interstitial (pH = 7.4) and intracellular (pH = 7.0)). At equilibrium, I would expect the unbound concentration of the neutral form to be equal between the interstitial and intracellular sub-compartments, while the total free concentration (ionized + neutral forms) to be different, due to the pH differences.

When I simulate, however, the unbound concentration in the interstitial and intracellular spaces overlap, which is counter intuitive to me given what I mentioned earlier. I have attached a screenshot of the simulation I created. The picture represents the concentration time curve for the unbound concentration of erythromycin in the interstitial and intracellular spaces for the spleen.

I have noticed that PK-Sim calculates the unbound concentration in these sub-compartments by multiplying the total concentration in the sub-compartment by a partition coefficient water/container, which I believe represents the free fraction in that compartment. This behavior led me to the following questions:

1. When PK-Sim displays the free concentration of a drug in a sub-compartment, is it showing the total unbound concentration or the unbound concentration of the neutral form, in case of drugs that are ionizable?

2. If it is displaying total free concentration, shouldn't the values be different or I am missing something else?

3. How are the partition coefficients water/compartment for the intracellular space calculated and how are they linked to the partition coefficient for the tissue at steady-state predicted by the different tissue composition methods?

Best,

Icaro S Perovani

[github-actions[bot]]

🤖 Discussion Assistant: I found some similar discussions that might be helpful:

• Questions regarding fraction of drug recycled and passive transport of drug (75% similar)
• Interstitial unbound concentrations and endothelial membrane (74% similar)
• When estimating intrinsic CL with MM kinetics optimized in PK-Sim, is the derived intrinsic CL for "unbound" or "total" drug? (74% similar)
• Drug penetration into interstitial space (73% similar)
• Rodgers and Rowland Kp algorithm - Double accounting for protein binding contribution in tissue? (73% similar)