Fig. 5. Role of extraction ratio in the influence of altered intrinsic clearance on drug disposition. Solid lines show the theoretical relationship between the area under the plasma time–concentration time curve (AUC) and the inhibition of intrinsic clearance (expressed as ratios relative to the uninhibited state) for low-extraction drugs (alfentanil; hepatic extraction ratio [E^H]= 0.14), intermediate-extraction drugs (midazolam; E^H= 0.38), and high-extraction drugs (fentanyl; E^H= 0.85, based on values from studies in volunteers 9–11), calculated as described in Materials and Methods. The clinical consequences (change in AUC) of inhibiting hepatic intrinsic clearance depend on the extraction ratio, with the disposition of high-extraction drugs comparatively less affected by changes in intrinsic clearance. Ratios of plasma AUC (or observed clearance ratios, if AUC data were not available) were determined from published data for erythromycin (⋄; the erythromycin–fentanyl interaction has not been studied, so data for sufentanil, also a high-extraction drug, are shown instead), 27,40,41propofol (○), 42diltiazem (•), 43fluconazole (▵), 31,44itraconazole (▾), 10,44ritonavir (▴), 11troleandomycin, 6,13and multidose troleandomycin (this investigation) and from supplemental data for itraconazole provided by Klaus Olkkola, M.D. (Associate Professor, Department of Anaesthesia and Intensive Care Medicine, Helsinki University Central Hospital, Helsinki, Finland; written communication, December 2001). Measured AUC ratios (ordinate) are plotted where they intersect the theoretical lines, which then provides predicted ratios for intrinsic clearance (abscissa). Although the effect of a given inhibitor on AUC will vary with the substrate, the inhibitor should cause similar reductions in intrinsic clearance. This is seen with diltiazem, fluconazole, itraconazole, and troleandomycin.