The A in ADME

In this book we will focus on physicochemical profiling in support of improved prediction methods for absorption, the A in ADME. Metabolism and other components of ADME will be beyond the scope of this book. Furthermore, we will focus on properties related to passive absorption, and not directly consider active transport mechanisms. The most important physicochemical parameters associated with passive absorption are acid-base character (which determines the charge state of a molecule in a solution of a particular pH), lipophilicity (which determines distribution of a molecule between the aqueous and the lipid environments), solubility (which limits the concentration that a dosage form of a molecule can present to the solution and the rate at which the molecule dissolves from 

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When solving the model problem concerned, the transition from the A th iteration to the (k + l)th iteration is performed either in 9 steps or in 26 steps 5 operations of addition and 4 operations of multiplication during the course of the explicit Chebyshev s method and 12 operations of addition and 14 operations of multiplication in the case of ADM in connection with the double elimination (first, along the rows and then along the columns). This provides reason enough to conclude that in the case of noncommutative operators the first method is rather economical than the second one. Both 1 1... 

Traditional octanol-water distribuhon coefficients are shll widely used in quan-titahve structure-achvity relationship (QSAR) and in ADM E/PK studies. However, alternahve solvent systems have been proposed [80]. To cover the variabihty in biophysical characterishcs of different membrane types a set of four solvents has been suggested, somehmes called the critical quartet [81]. The 1,2-dichloroeth-ane-water system has been promoted as a good alternative to alkane-water due to its far better dissolution properties [82, 83], but may find little applicahon because of its carcinogenic properties. 

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]. 

More recently, the bottleneck of drug research has shifted from hit-and-lead discovery to lead optimization, and more specifically to PK lead optimization. Some major reasons are (i) the imperative to reduce as much as feasible the extremely costly rate of attrition prevailing in preclinical and clinical phases, and (ii) more stringent concerns for safety. The testing of ADME properties is now done much earlier, i.e. before a decision is taken to evaluate a compound in the clinic. 

Drug candidates that are intended for oral dosing need to have good ADME properties so that they can be dosed once or twice daily. The drug should be well absorbed, survive first pass metabolism, and have sufficiently low clearance. At the lead identification stage, the primary in vitro ADME assays employed are those that assess permeability and metabolic stability. There are a variety of assays available for both parameters, as described in the previous chapter. 

Drug therapy is a dynamic process. When a drug product is administered, absorption usually proceeds over a finite time interval, and distribution, metabolism, and excretion (ADME) of the drug and its metabolites proceed continuously at various rates. The relative rates of these ADME processes determine the time course of the drug in the body, most importantly at the receptor sites that are responsible for the pharmacological action of the drug. 

This book is written for the practicing pharmaceutical scientist involved in absorption-distribution-metabolism-excretion (ADME) measurements who needs to communicate with medicinal chemists persuasively, so that newly synthesized molecules will be more drug-like. ADME is all about a day in the life of a drug molecule (absorption, distribution, metabolism, and excretion). Specifically, this book attempts to describe the state of the art in measurement of ionization constants (p Ka), oil-water partition coefficients (log PI log D), solubility, and permeability (artificial phospholipid membrane barriers). Permeability is covered in considerable detail, based on a newly developed methodology known as parallel artificial membrane permeability assay (PAMPA). 

As ADME/PK has become incorporated into drug discovery it has become necessary to reconsider the purpose of the studies. If the science is really going to reduce the attrition rate in development, then it is essential for the studies to allow predictions of the PK in man to be made. This means predicting the likely size and frequency of the dose. A review of the top 10 medicines of 1999 (Table 6.1) shows all of them to be once-a-day compounds. It is clear that to be best in class , and to be able to maintain that position as follow-up compounds come along, it seems probable that a compound will need to be suitable for once a day dosing. 

High-throughput laboratories have turned to assay automation, N-in-one (sample pooling) analysis strategies, and elaborate set-ups for parallel chromatography30 33 to increase capacity and decrease turn-around time. Despite the relatively fast speed of HPLC/MS, this step still creates a bottleneck in ADME work flow. Xu et al.32 reported a fast method for microsomal sample analysis that yields 231 data points per hour using a complex eight-column HPLC/MS set-up. 

For a drug to interact with a target, it has to be present in sufficient concentration in the fluid medium surrounding the cells with receptors. Pharmacokinetics (PK) is the study of the kinetics of absorption, distribution, metabolism, and excretion (ADME) of drugs. It analyzes the way the human body deals with a drug after it has been administered, and the transportation of the drug to the specihc site for drug-receptor interaction. For example, a person has a headache and takes an aspirin to abate the pain. How does the aspirin travel from our mouth to reach the site in the brain where the headache is and act to reduce the pain ... 

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