Graphical Model for Estimating Oral Bioavailability of Drugs in Humans and Other Species from Their Caco-2 Permeability and in Vitro Liver Enzyme Metabolic Stability Rates

Abstract

This paper describes a graphical model for simplifying in vitro absorption, metabolism, distribution, and elimination (ADME) data analysis through the estimation of oral bioavailability (%F) of drugs in humans and other species. This model integrates existing in vitro ADME data, such as Caco-2 permeability (P(app)) and metabolic stability (percent remaining - %R) in liver S9 or microsomes, to estimate %F into groups of low, medium, or high regions. To test the predictive accuracy of our model, we examined 21 drugs and drug candidates with a wide range of oral bioavailability values, which represent approximately 10 different therapeutic areas in humans, rats, dogs, and guinea pigs. In vitro data from model compounds were used to define the boundaries of the low, medium, and high regions of the %F estimation plot. On the basis of the in vitro data, warfarin (93%), indomethacin (98%), timolol (50%), and carbamazepine (70%) were assigned to the high %F region; propranolol (26%) and metoprolol (38%) to medium %F region; and verapamil (22%) and mannitol (18%) to the low %F region. Similarly, the %F of 11 drug candidates from Elastase Inhibitor, NK1/NK2 antagonist, and anti-viral projects in rats, guinea pigs, and dogs were correctly estimated. This model estimates the oral bioavailability ranges of neutral, polar, esters, acidic, and basic drugs in all species. For a large number of drug candidates, this graphical model provides a tool to estimate human oral bioavailability from in vitro ADME data. When combined with the high throughput in vitro ADME screening process, it has the potential to significantly accelerate the processes of lead identification and optimization.

PQ-69, a novel and selective adenosine A1 receptor antagonist with inverse agonist activity

“…The pharmacokinetic parameters were calculated using a noncompartmental model in WinNonlin Professional (Version 5.2.1, Pharsight Corp; Mountain View, CA, USA). In vitro metabolic stability of PQ-69 and DPCPX was investigated using rat and human liver microsomes in procedures similar to those previously described [15]. The incubations (5 μM parent drug, 0.5 mg/ml microsomal protein, 0.1 M phosphate buffer) were started by the addition of 1 mM NADPH solution after a 5-min preincubation at 37°C and were terminated after 60 min.…”

The role of pharmacokinetics and pharmacodynamics in phosphodiesterase-5 inhibitor therapy

“…Absorption in vivo is a complex phenomenon, involving several possible mechanisms, although passive diffusion has been identified as the predominant mechanism of gastrointestinal absorption for most commercial drugs. 4 The most relevant factors that regulate the passive diffusion of drugs across the gastrointestinal mucosa are their physicochemical properties, including lipophilicity, solubility, polarity and ionization status. Physiological characteristics such as gastric emptying time and pH conditions throughout the gastrointestinal tract (GIT) also affect oral absorption.…”

A label-free microfluidic assay to quantitatively study antibiotic diffusion through lipid membranes

“…It is estimated that between 80-95% of commercial drugs are absorbed primarily by passive diffusion 17,18 , and thus an assay to quantify permeability coefficients due to passive diffusion would be of great interest to the pharmaceutical industry. It has previously been demonstrated that giant vesicles are stable in microfluidic flows, and show potential for membrane transport studies 9 .…”