In vitro–in vivoextrapolation (IVIVE) for predicting human intestinal absorption and first-pass elimination of drugs: principles and applications

Abstract

Oral administration remains the preferred dosing method in clinical practice and drug development. Oral bioavailability (F) is a function of the fraction absorbed (Fabs), gastrointestinal or gut wall availability (FG), and hepatic availability (FH). Therefore, predicting intestinal absorption (Fabs) and first-pass elimination (FG and FH) from in vitro data may facilitate the selection of more orally bioavailable drug candidates in earlier stages of drug discovery and development. This review provides an overview of the determinants of intestinal absorption and first-pass elimination of drugs and focuses on the principles and applications of conventional in vitro--in vivo extrapolation (IVIVE) methods to predict Fabs, FG, and FH in humans.

Physiologically Based Pharmacokinetic (PBPK) Modeling and Simulation Approaches: A Systematic Review of Published Models, Applications, and Model Verification

“…While interspecies scaling allows predictions of the human volume of distribution, its utility in the prediction of human clearance is limited due to species differences in the expression and substrate specificity of drug metabolizing enzymes and transporters (Obach et al, 1997;Di et al, 2013). Instead, IVIVE tools have been developed to predict hepatic bioavailability and whole organ clearances using in vitro intrinsic clearance, protein binding and permeability data and in vivo blood flows (Houston, 1994;Iwatsubo et al, 1997;Obach et al, 1997;Lombardo et al, 2013b;Cho et al, 2014). While further efforts are needed to improve IVIVE, particularly for transporters and non-P450 enzymes, IVIVE has become an important tool in the process of predicting human exposures and effective dosages.…”

Development of HPLC Method for the Determination of Buspirone in Rat Plasma Using Fluorescence Detection and Its Application to a Pharmacokinetic Study

“…7,8) However, little information is available regarding important pharmacokinetic issues that include the exact reason for the low bioavailability, kinetics of organ clearance, and mechanisms of elimination of buspirone in animals or humans. 9) Therefore, development of analytical tools for quantification of buspirone in various biological fluids will contribute to the progress of mechanistic pharmacokinetic and pharmacological studies of buspirone in a pre-clinical or clinical setting.…”

Metabolic interactions of magnolol with cytochrome P450 enzymes: uncompetitive inhibition of CYP1A and competitive inhibition of CYP2C

“…However, some herbal extracts and phytochemicals have been reported to modulate drug metabolizing enzyme activity, leading to herb-drug interactions which may cause adverse reactions such as toxicity and therapeutic failure [2][3][4] . Among various drug metabolizing enzymes, cytochrome P450 monooxygenase (CYP) is typically involved in clinically significant interactions between prescribed drugs and herbs [5][6][7] . Grapefruit (Citrus paradisi), St. John's wort (Hypericum perforatum), ginkgo (Ginkgo biloba) and licolice (Glycyrrhiza glabra) have all been reported to alter the CYP-mediated metabolism and efficacy of anticoagulants, anticancer drugs, antiretroviral drugs, antihyperlipidemic drugs, immunosuppressants and/or antidepressants [8][9][10][11][12][13][14] .…”