Retrograde calculation for CYP intrinsic clearance

[regulus92]

Hello, everyone. I am stuck in a problem. I failed to work out the same values of CYP intrinsic clearance provided in some references according to a retrograde method (1). See the following tramadol example As I see, CL_int,H=CL_H×Q/(Q-CL_H)×1/fu, and CL_int,CYP = relative contribution×CL_int,H/liver weight/CYP liver concentration. So from PK-Sim setting, I calculated CL_int,2D6 0.38 μl/min/pmol. Where am I wrong? Besides, a 25 year-old European individual gives liver blood flow of 0.43 L/min in PK-Sim, which I think is too low. I can't find the source of a 99.15 L/h hepatic blood flow. The following example (2) makes me more confused. Simcyp software seems to have a retrograde calculation tool but I haven't find its algorithm. Sorry for too many questions. I really appreciate your help. Thank you very much.

1. T'Jollyn H, Vermeulen A, Van Bocxlaer J. PBPK and its Virtual Populations: the Impact of Physiology on Pediatric Pharmacokinetic Predictions of Tramadol. AAPS J. 2018;21(1):8.
2. Johnson TN, Zhou D, Bui KH. Development of physiologically based pharmacokinetic model to evaluate the relative systemic exposure to quetiapine after administration of IR and XR formulations to adults, children and adolescents. Biopharm Drug Dispos. 2014;35(6):341-52.

[jzq90]

Hi,

0.43 L/min is hepatic artery blood flow. Below this part in PK-Sim, there is a portal vein blood flow rate 1.2 L/min. The sum of these two values is 1.63 L/min =97.8 L/h.

As for CLint,2D6, what's the value of CLH?

[regulus92]

Thank you for your reply. CL_H=CL_total-CL_renal=25.5 L/h. Anyway, the second quetiapine example provides values that are far from our calculations.