Absorption, distribution, metabolism, and elimination ADME

The nature of toxic damage produced by a chemical, the part of the body where that damage occurs, the severity of the damage, and the likelihood that the damage can be reversed, all depend upon the processes of absorption, distribution, metabolism and elimination, ADME for short. 

Pharmacokinetics (PK) is the science that describes the time course of a circulating drug concentration in the body resulting from administration of a certain drug dose. In comparison, pharmacodynamics (PD) is the science that describes the relationship of the time course of drug concentration and the drug effects in the body (Meibohm and Derendorf, 1997). Key determinants of the PK of a drug include absorption, distribution, metabolism, and elimination (ADME) (Lin et al., 2003), as discussed in Chapter 1. 

The pharmacokinetic phase of drug action includes the Absorption, Distribution, Metabolism and Elimination (ADME) of the drug. Many of the factors that influence drug action apply to all aspects of the pharmacokinetic phase. Solubility (see Section 3.3), for example, is an important factor in the absorption, distribution and elimination of a drug. Furthermore, the rate of drug dissolution, that is, the rate at which a solid drug dissolves in the aqueous medium, controls its activity when a solid drug is administered by enteral routes (see Section 2.6) as a solid or suspension. 

Toxicokinetics describe Absorption, Distribution, Metabolism and Elimination (ADME) of a chemical in humans, experimental animals or cellular systems. Of specific importance for interpretation of animal studies and for extrapolation of hazards between species is the comparative information on the exposure and the dose that reaches the critical target. 

Drug transport to the brain depends on various parameters. The amount of drag available for transport across the BBB depends upon its systemic pharmacokinetics [represented by absorption, distribution, metabolism, and elimination (ADME) see also Figure 1]. For drags that can easily pass the BBB, blood flow is a limiting factor, whereas for other drags, BBB-permeability is restrictive. In addition, the cardiac output to the brain seems not to be the main determinant for blood flow, but rather the local blood flow and the capillary flow area. In vivo capillary flow was... 

Myalgias related to statin use are quite common, occurring in up to 10 % of patients exposed [19]. Clinicians often measure circulating levels of nonspecific markers of myocyte damage (e.g., CK) to estimate severity. Myalgias accompanied by a mild elevation in serum CK level occur in approximately 1 % of patients exposed [20, 21], Myopathy (CK >10-fold upper limit of normal) is less common, 0.1 %, and rhabdomyolysis (CK >50-fold upper limit of normal) is extremely rare [14, 15]. Graham and colleagues surveyed more than 250,000 statin-exposed patients, and reported rhabdomyolysis rates of 0.000044 events per person-year [18]. Similar rates have been observed for more than 100,000 first-time statin users followed in the UK over a course of 20 months [22], Event rates increase when statins are used in the presence of other medications known to alter their absorption, distribution, metabolism, and elimination (ADME) [23, 24], Event rates also increase with comorbidity (e.g., thyroid disease) [21, 25]. 

The clinical severity of statin-induced muscle toxicity is clearly influenced by variability in enzymes modulating statin disposition (absorption, distribution, metabolism, and elimination, ADME) (Fig. 1) [40], While many statins undergo phase I oxidation (atorvastatin, fluvastatin, lovastatin, simvastatin), the impact of phase I oxidation on others (pitavastatin, pravastatin, rosuvastatin) is very limited [41],... 

Pharmacokinetics—the study of the kinetics associated with drug absorption, distribution, metabolism, and elimination (ADME). Pharmacodynamics—the study of the effect of a drug and its mechanism of action. 

Lead generation offers an opportunity to initiate the drug discovery process with the best possible chemical starting points. In this phase, a project can survey a wide diversity of compoimds to identify novel compounds that balance potency with appropriate physicochemical, absorption, distribution, metabolism, and elimination (ADME) properties and a low risk of toxicity. Later in the optimization process, when locked in to a small number of series, it may be much more difficult to improve one property without having a negative effect on another. 

Recent developments in the in-vivo characterization of putative vanadium(IV) pharmaceuticals have focused on completion of a metabolic model that fully describes the Absorption, Distribution, Metabolism, and Elimination (ADME) of exogenous vanadium [23]. Such knowledge would assist in the development of compounds with increased efficacy, as direct in-vivo/in-vitro antidiabetic assays combined with complete ADME data for the putative complex would lead to an understanding of the structure/function relationships that determine a complex s insulin-enhancing capability. 

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