Figure 9.

Singular value decomposition analysis of binding of ketoconazole to cyotochrome P450 (P450) 3A4. The final concentrations (after mixing) of P450 3A4 and clotrimazole were 2 and 15 μM, respectively. The OLIS GlobalWorks model used was a three-species 1 → 2 → 3 (A → B → C in software) fast/slow rate model, where the unbound P450 3A4 is not included, and 1, 2, and 3 are three different P450 3A4·ketoconazole complexes (this sequence would begin ∼100 ms after mixing P450 3A4 and ketoconazole; Fig. 6, C–D). A, spectra of the three intermediate species (species 1—blue; species 2—red, and species 3—black); B, time courses of the three species (same color pattern), plus a plot of the total absorbance accounted for at each time point; C, total residual plot for the kinetics traces. The data were collected in the Show Pre-trigger Mode, with 2.1 s of data from the previous run (completed reaction) showing prior to mixing (not reflected in part B). See Table 1 for calculated rates.