The change in AUC as estimated by calculating the effect of the respective inhibitor on the rate of metabolism as derived from the Michaelis-Menten equations Equations 1a and 1b use Cmax as inhibitor concentrations. Equation 2 uses an estimated portal vein concentration as inhibitor concentration (from Table 1). All p values for the observed AUC ratio were >0.5.
Substrate | Inhibitor | Eq. 1a a | Eq. 1b b | Eq. 3or 4c | Observed AUC-Ratio (90% CI) |
|---|---|---|---|---|---|
| Diclofenac | Tolbutamide | 3.8 | 1.0 | 1.1 | 0.93 (0.7—1.24) |
| Diclofenac | Ibuprofen | 2.2 | 1.0 | 1.1 | 0.99 (0.77—1.26) |
| Diclofenac | Fluvastatin | 6.3 | 2.0 | 1.7 | 1.07 (0.82—1.41) |
| Tolbutamide | Diclofenac | 1.7 | 1.6 | 1.0 | 1.01 (0.85—1.20) |
| Ibuprofen | Diclofenac | 1.6 | 1.4 | 1.0 | 1.03 (0.84—1.26) |
| Fluvastatin | Diclofenac | 2.6 | 1.0 | 1.0 | 1.08 (0.81—1.45) |
CI, confidence interval.
↵ a Equation 1a: AUC ratio = v(I)/v(control) = 1/ (1 + I/Ki), I = Cmax total; Ki total
↵ b Equation 1b. The free fractions for the inhibitor (Iu) and Ki (Ki,u) are used
↵ c Equation 3: AUC ratio = 1/((fm/1 + Iu/Ki) + 1 — fm) (fluvastatin); eq. 4: AUC ratio = 1/(fh·fm(1/1 + Iu/Ki) + (1 — fh·fm)) (diclofenac, tolbutamide, ibuprofen)