ADME studies

Metabolite profiling involves detection, quantitative analysis, and structural elucidation of drug metabolites present in a biological matrix using HPLC coupled with a UV detector, radioactivity detector, and/or mass spectrometer. 

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Another relatively new lipophilicity scale proposed for use in ADME studies is based on MEKC [106]. A further variant is called BMC and uses mobile phases of Brij35 [polyoxyethylene(23)lauryl ether] [129]. Similarly, the retention factors of 16 P-blockers obtained with micellar chromatography with sodium dodecyl sulfate as micelle-forming agent correlates well with permeability coefficients in Caco-2 monolayers and apparent permeability coefficients in rat intestinal segments [130]. 

An approach that can be used in determining ADME/PK parameters that is simple to execute and gives confidence that the whole dose is accounted for, is to use a radiolabel. This has been the standard approach for development ADME studies for many years. The common isotopes used are 14C or 3H (tritium). 

The results of such studies not only help to identify any toxic effects, but also point to the most appropriate method of drug administration, as well as the most likely effective dosage regime to employ. Generally, ADME studies are undertaken in two species, usually rats and dogs, and studies are repeated at various different dosage levels. All studies are undertaken in both males and females. 

Before this topic is left behind, it should be noted that statistical significance is by no means the only consideration in interpretation of toxicity test results. If, in our particular case, the pathologist were to inform us that the brain lesion observed was extremely unusual or rare, we should certainly hesitate to dismiss our concerns because of lack of statistical significance. The toxicologist needs equally to understand biological significance, and, in this case, would almost certainly pursue other lines of investigation (perhaps an ADME study to determine if the pesticide reaches the brain, or a toxicity test in other species) to determine whether the effect was truly caused by the chemical. 

Typically, ADME studies are included in the battery of tests used to characterize the toxicity of chemicals, as well as other studies designed to trace the underlying molecular and cellular events that lead to toxicity. These studies of toxic mechanisms take many forms, and are better viewed as research studies no general characterization of them will be made here, but some of the things such studies can reveal to aid understanding of risk will be mentioned at appropriate places in the remaining sections of the book. 

Olah, T. V The development and implementation of bioanalytical methods using LC-MS to support ADME studies in early drug discovery and candidate selection. Ernst Schering Res Found Workshop 2002, 155-183. 

Using data from a human radiolabel ADME study in which metabolic pathways are fully delineated, in combination with in vitro data that identifies which enzymes are responsible for which metabolic pathways, values of can be estimated. 

The basic material a regulator uses in reproductive toxicity risk assessment for pesticides is provided in the study reports submitted by the applicant. This includes ADME studies, acute toxicity. 

PYA copolymer Bioavailability enhancer Single-dose toxicity (in rat and dog) and maximum tolerated dose/short-term (2wks—oral) (in rat and dog) toxicity as well as 2 in vitro and 1 in vivo genotoxicity studies. ADME studies with 14C-labelled material are underway and a 3-6 mo toxicity study in the rat is planned No adverse effects seen to date 41... 

Single and repeat dose toxicity studies (with later mainly in the rat and dog by oral or intravenous route and up to 1 year duration), reproduction toxicity (embryo-foetal studies in the rat and rabbit), battery of genotoxicity assays, carcinogenicity studies (by diet route in mouse and rat) plus ADME studies (single and multiple dosing)... 

Perform radiolabeled human ADME study as early as possible to define a major circulating metabolite. 

Absorption, distribution, metabolism, and excretion (ADME) studies... 

ADME studies (adsorption, distribution, metabolism and excretion)... 

During the development of rivaroxaban 1, Pleiss et al. at Bayer Health Care prepared [14C]-radiolabeled rivaroxaban,22 which was required for clinical studies of drug absorption, distribution, metabolism, and excretion (ADME studies). The approach taken for the synthesis of l4C labeled rivaroxaban 38 relies on the previously reported synthesis. In the presence of EDC HCl and HOBT, 4- 4-[5S)-5-(aminomethyl)-2-oxo-l,3-oxazolidin-3-yl]phenyl -morpholin-3-one 22 was coupled with 5-chloro-2-thiophene [14C]-carboxylic acid 37 and was purified using chiral HPLC to afford the [l4C]-radiolabelled rivaroxaban 38 in 85% yield with high chemical and radiochemical purity and with an enantiomeric excess of > 99% ee (Scheme 5). Meanwhile, the metabolite M-4 of rivaroxaban (compound 39) was prepared from 5-chlorothiophenecarboxylic acid chloride 23 and [14C]glycine in 77% yield (Scheme 6). 

ADME Studies Absorption, distribution, metabolism, and excretion studies were conducted for 24,21,17, and 19 out of the 34 biopharmaceuticals, respectively. No radiolabeled proteins were used for 20, 2,1, and 13 out of the 34... 

A series of pharmacokinetic and ADME studies was performed with imi-glucerase in order to assess clearance and targeting of imiglucerase in vivo. Because there was no suitable animal model for Gaucher disease, these studies were performed in normal animals. 

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