Presentation of a modified dispersion model (MDM) for hepatic drug extraction and a new methodology for the prediction of the rate-limiting step in hepatic metabolic clearance

The main objectives were to investigate the roles of and interplay between determinants of hepatic clearance (CLH) in humans, to develop a methodology and reference system for the evaluation and prediction of the rate-limiting step in CLH, and to update the dispersion model and compare it with traditionally used liver extraction models. The new methodology enables predictions of the hepatic uptake and CLH, dissociation, and rate-limiting step. In general, absorption, dissociation and diffusion are comparably rapid processes, and metabolism is rate-limiting. The liver appears to have a high passive uptake capacity. The Modified Dispersion Model (MDM) has a dispersion number of 0.5 and a distribution factor (dƒ = 0.87) for the correction of a longer hepatic transit time of unbound molecules and the exclusion of the hidden unbound fraction within erythrocytes. Liver models are functionally equivalent at low CLH, but differ for highly extracted compounds. Well-stirred and parallel-tube models demonstrate the greatest difference in performance, for example, 6- and 800 000-fold differences in the estimated in vivo intrinsic CLH and predicted oral bioavailability of the high CLH drug naloxone, respectively. The roles of and interplay between determinants of CLH have been further clarified and can now be better predicted. Apparent advantages with the MDM include its scientific rationale and intermediate/ balanced performance.