Fig. 1.
Schematic representation of the physiological population PK model for midazolam and the metabolite 1-OH-midazolam. The extraction of midazolam is defined by the well-stirred model in the liver and the ‘Qgut’ model in the gut wall. E = extraction ratio, F = bioavailability in the gut wall (gut, G) and the liver (hepatic, H). CLint is the whole-organ intrinsic clearance in the gut wall and liver, Ka indicates the absorption rate constant and the fraction unbound in blood and gut wall are described with fu,B and fu,G respectively. Blood flows are represented by Q; in the micro villi (Qvilli), portal vein (QPV), hepatic artery (QHA) and liver (Qh). Distribution between central and peripheral (Periph.) compartments is estimated by inter-compartmental clearance Q1 and Q2 for the two peripheral compartments for midazolam. Parameters describing the metabolite are indicated with the subscript M.