A method for analyzing the ADME/PK properties

Medicilon's pharmacokinetics department offers the clients a broad spectrum of high quality of services in the areas of in vitro ADME, in vivo pharmacokinetics and bioanalysis services, ranging from small molecules to large molecules, such as protein and antibody. The animal species involved in our services are non-human primate, canine, mice, rat, rabbit and hamster. Meanwhile, non-human primate experimental platform and isotope platform for protein/antibody are certified by the Shanghai Government. Email:marketing@medicilon.com.cn Web:www.medicilon.com

A method for analyzing the ADME/PK properties of a mixture of compounds is (1) perfusing an animal or organ with a perfluorocarbon emulsion blood substitute, (2) administering the mixture of test compounds, (3) withdrawing an aliquot of the perfusate, (4) disrupting the emulsion, and (5) analyzing the aqueous phase of the perfusate for the concentration of test compounds.

This invention relates to the fields of pharmacokinetics and pharmacological research. More specifically, the invention describes the concept of using perfluorocarbon emulsions for examining the ADME/PK (absorption, distribution, metabolism, excretion and pharmacokinetics) properties of chemical mixtures in animals and a method for preparing the emulsions for direct analysis by techniques such as high performance liquid chromatography (HPLC), mass spectrometry and capillary electrophoresis.

BACKGROUND OF THE INVENTION

Drug development begins with the identification of a lead compound, based on the ability of the compound to exhibit a desired biological effect, such as the ability to inhibit bacterial growth, inhibit the activity of a target enzyme, increase or modulate the uptake of neurotransmitters, and the like. Biological activity is typically determined on the basis of in vitro experimentation or assays designed to rapidly identify candidate drugs. Typically, only a small percentage of the compounds tested will demonstrate sufficient activity and selectivity to merit further investigation.

Once a candidate or lead compound has been identified and selected for further development, its ADME/PK characteristics are determined. ADME/PK study concerns the absorption, distribution, metabolism, excretion and pharmacokinetics of drugs in the body. The ADME/PK properties of a drug are critical, and often serve to distinguish pharmaceutical products from mere lead compounds. For example, a drug that is poorly absorbed orally may require intravenous (or other parenteral) administration to be effective, which may be unacceptable for the condition to be treated. A compound effective as an antibiotic may be ineffective to treat bacterial meningitis if its distribution does not carry it to the central nervous system. A compound that is rapidly metabolized and/or excreted may not reside in the body long enough to serve its intended purpose. These properties are all independent of the drug candidate's in vitro activity, and are difficult or impossible to predict based on current information. The complex factors that influence ADME/PK make it hard to model accurately, and necessitate the use of living tissues and research animals before a compound may proceed with clinical trials.

To enhance the speed of drug discovery and reduce the number of animals required, it is desirable to characterize the ADME/PK of mixtures of lead compounds (rather than single compounds) in procedures that involve either living animals (i.e., in vivo), or isolated organs or organ systems from animals.

In in vivo analyses of ADME/PK assay, plasma is generally the biophase used as the analytical endpoint. Measurement of individual drug candidates in plasma typically involves a unique extraction method based on the physicochemical properties of each molecule, in order to separate and quantify the compound from the numerous plasma components. Optimization of one plasma extraction method for all components of a chemical mixture poses a major problem for rapid screening.

SUMMARY OF THE INVENTION

We have now invented a method for improving the ADME/PK analysis of candidate compounds, by replacing the blood of a test animal or tissue with an emulsified blood substitute, administering a test compound, and analyzing the resulting blood substitute. Preferably, the test compound is administered as a mixture of test compounds.

Another aspect of the invention is the method for designing libraries of pharmaceutical candidates based on ADME/PK properties.