Table 4

Prediction of the in vivo interaction between metoprolol and paroxetine, based on in vitro inhibition constants of paroxetine corrected for futile binding (K_i) and the estimated in vivo hepatocytosolic inhibitor concentrations ([I])

Substrate		K_i	[I]^4-a	f_m	Predicted AUC Ratio^4-b	Observed AUC Ratio^4-c
		μM	μM
Unbound
(R)-Metoprolol	α-Hydroxylation	0.045	0.11	0.1
	O-Demethylation	0.028	0.11	0.6
					2.2	10.5 (4.6–21.4)
(S)-Metoprolol	α-Hydroxylation	0.044	0.11	0.1
	O-Demethylation	0.053	0.11	0.6
					1.9	6.7 (3.2–14.4)
Total
(R)-Metoprolol	α-Hydroxylation	0.045	2.14	0.1
	O-Demethylation	0.028	2.14	0.6
					3.2	10.5 (4.6–21.4)
(S)-Metoprolol	α-Hydroxylation	0.044	2.14	0.1
	O-Demethylation	0.053	2.14	0.6
					3.2	6.7 (3.2–14.4)

↵4-a Estimated according to eq. 5.
↵4-b Calculated according to eq. 6.
↵4-c In vivo observed AUC ratio (range) in the presence and in the absence of paroxetine (Hemeryck et al., 2000).