. 2015 Jul 25;17(6):1376–1387. doi: 10.1208/s12248-015-9803-z

Table I.

Criteria by which CYP contributions in the retrograde model are assessed. CYP2D6 involvement was estimated by comparing hepatic clearance fold increase from PM to EM between predictions and in vivo. CYP2B6-CYP3A4 involvement was estimated by comparing AUCinduced/AUCcontrol ratios between predictions and observations

The retrograde model for CYP involvement in tramadol metabolism
	Criterion	In vivo observation	RG PBPK model prediction	Percent involvement in Hep CL
CYP2D6	Hepatic CL fold increase from PM to EM	1.74^a	1.73	48% CYP2D6
CYP2B6 CYP3A4	AUC_Ind/AUC_control in rifampicin-tramadol DDI clinical trial simulation	0.58^b	0.61– > 0.62	0– > 10% CYP2B6 52– > 42% CYP3A4

The retrograde model for CYP involvement in tramadol metabolism

Criterion

In vivo observation

RG PBPK model prediction

Percent involvement in Hep CL

CYP2D6

Hepatic CL fold increase from PM to EM

1.74^a

1.73

48% CYP2D6

CYP2B6

CYP3A4

AUC_Ind/AUC_control in rifampicin-tramadol DDI clinical trial simulation

0.58^b

0.61– > 0.62

0– > 10% CYP2B6

52– > 42% CYP3A4

PM/EM poor or extensive metabolizer, RG retrograde, DDI drug-drug interaction

^a(31)

^b(33)