TABLE 4

Predicted M2 (i.e., clopidogrel active metabolite H4) exposure ratios in CYP2C19 PMs vs. EMs using static and dynamic models

Compared with the general situation schematized in Fig. 1, CYP2C19 was considered to be involved in the two metabolic steps to mimic the clopidogrel situation. With use of the static model, M2 exposure ratios were determined using the static model with eqs. 7 or 8 and using Simcyp as described under Materials and Methods. In the clopidogrel situation, F_{M, X}, F_{M, Z}, and F_{M, 2C19} represent CYP450-dependent pathways; F_{M, a} and F_{M, b} represent the undefined clearance (esterase for F_{M, a}). Several studies have shown that F_{m, a} (esterase) is high compared with CYP450-dependent pathways at the first metabolic step and that F_{m, b} would be equivalent at the second metabolic step (Kazui et al., 2010; Gurbel et al., 2009). In the six simulations, F_m values were selected to mimic this situation. Data are arithmetic means (S.D.).