Prediction of human pharmacokinetics—gut-wall metabolism

Abstract

Intestinal mucosal cells operate with different metabolic and transport activity, and not all of them are involved in drug absorption and metabolism. The fraction of these cells involved is dependent on the absorption characteristics of compounds and is difficult to predict (it is probably small). The cells also appear comparably impermeable. This shows a limited applicability of microsome intrinsic clearance (CL int )-data for prediction of gut-wall metabolism, and the difficulty to predict the gut-wall CL (CL GW ) and extraction ratio (E GW ). The objectives of this review were to evaluate determinants and methods for prediction of first-pass and systemic E GW and CL GW in man, and if required and possible, develop new simple prediction methodology. Animal gut-wall metabolism data do not appear reliable for scaling to man. In general, the systemic CL GW is low compared with the hepatic CL. For a moderately extracted CYP3A4-substrate with high permeability, midazolam, the gut-wall/hepatic CL-ratio is only 1/35. This suggests (as a general rule) that systemic CL GW can be neglected when predicting the total CL. First-pass E GW could be of importance, especially for substrates of CYP3A4 and conjugating enzymes. For several reasons, including those presented above and that blood flow based models are not applicable in the absorptive direction, it seems poorly predicted with available methodology. Prediction errors are large (several-fold on average; maximum ~15-fold). A new simple first-pass E GW -prediction method that compensates for regional and local differences in absorption and metabolic activity has been developed. It has been based on human cell in-vitro CL int and fractional absorption from the small intestine for reference (including verapamil) and test substances, and in-vivo firstpass E GW -data for reference substances. First-pass E GW -values for CYP3A4-substrates with various degrees of gastrointestinal uptake and CL int and a CYP2D6-substrate were well-predicted (negligible errors). More high quality in-vitro CL int -and in-vivo E GW -data are required for further validation of the method.

Physiologically Based Predictions of the Impact of Inhibition of Intestinal and Hepatic Metabolism on Human Pharmacokinetics of CYP3A Substrates

“…where Q muc,i corresponds to the blood flow to intestinal mucosa of any given intestinal compartment 57. The total Q muc is estimated to 0.250 mL/min73 (Tab.…”

Prediction of human pharmacokinetics—biliary and intestinal clearance and enterohepatic circulation

“…The overall CL int,i is influenced by the amount/fraction of mature enterocytes involved (functionally mature cells are found at the villi tips), and the villous counter-current exchange system (which enables transport of molecules from arterioles to venules without accessing the enterocytes) (Fagerholm 2007e). Important intestinal efflux proteins, such as MDR1 (P-glycoprotein), MRP2 and BCRP, are not localized on the blood side of enterocytes (TP-search transport database, 2007), which indicates a potential for limited active intestinal active secretion capacity.…”

Cytochrome P450-mediated metabolism in the human gut wall

“…Several authors have suggested that mucosal blood flow rather than total intestinal blood flow or portal vein blood flow should be used when estimating intestinal metabolism 67–70 . Indeed, from an anatomical point of view, the one‐cell‐thick epithelial layer that contains the oxidative enzymes is supplied exclusively by the mucosal blood flow.…”