ADME processes

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. 

Fortunately, most ADME processes behave as pseudo-first-order processes—not because they are so simple, but because everything except the drug concentration is constant. For example, the elimination of a drug from the body may be written as follows ... 

Delivery systems have come a long way from piUs, syrups, and injectables. As we have discussed earlier, the ADME process means that most drugs admin-... 

This is a reflection of the increasing knowledge of the complexity of in viva systems, and also the current powerful computational resources to capture, analyze, interpret and model those systems. In view of this complexity, not only the development of genomics, proteomics and metabonomics databases, but also the development of systems biology methods helps us to understand the underlying mechanisms in any given ADME process [80]. 

The optimal administration of drugs in clinical practice is facilitated by effective application of the principles of clinical pharmacokinetics (PK) and pharmacodynamics (PD). Relationships between drug levels in the systemic circulation and various body compartments (e.g., tissues and biophase) following drug administration depend on factors governing drug absorption, distribution, elimination, and excretion (ADME). Collectively, the study of the factors that govern the ADME processes is termed pharmacokinetics. 

The development of predictive models for drug-likeness, frequent hitters, ADME processes, and toxicological endpoints has so far yielded a great deal of soft filters (see discussion above and the compilation of ADMET computational models by Yu and Adedoyin [66]), and the trend still continues to improve both accuracy and... 

Metabolism forms an important and probably least well-modeled part of the overall ADME process [57]. While metabolism/dearance may have a significant effect on oral bioavailabiiity, it is clearly ultimately responsible for the fate of xenobiotics,... 

This brief discussion ofthe components of bioavailability has shown that many of them are accessible experimentally and that in silico models may be built for the majority of them. Some recent reviews discuss the modeling of these components and other ADME processes [69-72]. It is by no means clear, however, and therefore remains a challenge as to how the individual components can easily be integrated into an overall prediction of oral bioavailability. 

Ouattara DA, Choi SH, Sakai Y, Pery AR, Brochot C (2011) Kinetic modelling of in vitro cell-based assays to characterize non-specific bindings and ADME processes in a static and a perfused fluidic system. Toxicol Lett 205 310-319. doi 10.1016/j.toxlet.2011.06.021... 

Pharmacokinetics is now challenged by the growing importance of transporters, a relatively new and potentially major factor in drug absorption, distribution, metabolism and excretion (the ADME process). Several years ago, passive diffusion was the main advanced process by which xenobi-otics were believed to move through body membranes. The... 

Delivery systems have come a long way from pills, syrups and injectables. As we have discussed earlier, the ADME process means that most drugs administered to us have tortuous paths to reach their targets, and in many instances the bioavailability is reduced. A traditional means to overcome the vagaries of ADME is to have larger doses or more frequent administrations. 

Before engaging in a detailed discussion of the PK modeling of ADME processes, it will be useful to discuss the basic mechanisms involved in the movement of chemicals from one location in the body to another. It will be shown that the physiochemical characteristics of the drug can have a large effect on this movement, particularly when it involves movement across a membrane or cellular barrier. In some cases, principles described in previous chapters for particular ADME processes will be discussed again here as they relate to other ADME processes (e.g., diffusion and active transport processes in Chapter 7 apply equally well to absorption and excretion processes) and PK model applications. Other aspects of chemical transport will be introduced that have not been thoroughly covered elsewhere in this book. 

All PK models involve several assumptions that allow the amazingly complex interactions between drug molecules and body systems to be simplified into a series of solvable equations. This section will describe the assumptions that are made or are inherent in each PK model. The implications of each assumption regarding application to real-world ADME processes will also be described. When the same assumption is applied to more than one model, it will be described in detail for the first model, with subsequent descriptions of the same assumption then simply referring back to the earlier description. 

The standard one-compartment bolus IV (or instantaneous absorption) model makes three inherent assumptions about the ADME processes that occur after drug delivery. The specific nature and implications of each of these assumptions are described in this section. 

As in all instantaneous absorption models, the entire absorbed dose of drug is taken to enter the systemic circulation instandy at time zero (< = 0). This provides an excellent approximation of the rapid drug delivery direcdy into the systemic circulation provided by a bolus IV injection, which truly occurs over a very short period of time (typically several seconds). However, this assumption does not actually require a strict interpretation of the word instantaneous. Even if an absorption process takes a substantial period of time (minutes or hours), it can still be approximated as instantaneous as long as absorption occurs quickly relative to other ADME processes. Thus, other routes of drug delivery besides a bolus IV injection can be approximated by instantaneous absorption if the time it takes for the absorption process to be essentially complete is very small compared to the half-life of elimination. The equations throughout most of this section are written specifically for a bolus IV injection, but modifications that can be employed to apply the equations to other drug delivery methods are described in Section 10.7.5. 

Plasma drug concentrations are determined by the relative rates of the ADME processes. ADME processes are represented in PK models by specific mathematical forms and parameters. 

All the standard PK models include a number of inherent assumptions about the ADME processes, including the universal assumption that elimination follows first-order or linear kinetics. 

To determine constraints that describes ADME processes succinctly ... 

From this discussion, the efficacy of a drug is not determined by its pharmacodynamic characteristics alone, but efficacy also depends, to a large extent, on the pharmacokinetic parameters of the drug, because ADME processes control the rate and extent to which an administered dose of a drug reaches its site of action. 

The ultimate goal is to design a drug molecule that exhibits the desired pharmacological effect as a result of the proper balance of ADME processes. Figure 9.37 illustrates how modification of a parent structure can influence the availability of a drug to the receptor site (53). 

After administering a dose, the change in drug concentration in the body with time can be described mathematically by various equations, most of which incorporate exponential terms (i.e. e or e ). This suggests that ADME processes are "first order" in nature at therapeutic doses and, therefore, drug transfer in the body is possibly mediated by "passive diffusion." Therefore, there is a directly proportional relationship between the observed plasma concentration and/or the amount of drug eliminated in the urine and the administered dose... 

Because of the complexity of ADME processes, an adequate description of the observations is sometimes possible only by assuming a simplified model the most useful model in pharmacokinetics is the compartment model. The body is conceived to be composed of mathematically interconnected compartments. 

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