Absorption, distribution elimination

Setting aside issues of compliance and administration errors, the therapeutic response experienced by each patient may be influenced by variations in pharmacokinetics (rate and extent of absorption, distribution, elimination) and pharmacodynamics (physiologic, pathologic, and genetic factors receptor interactions and tolerance). 

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. 

Chen, L. et al. Absorption, distribution, elimination of tea polyphenols in rats. Drug Metab. Dispos., 25, 1045, 1997. 

Drug Absorption, and Bioavailability ABSORPTION DISTRIBUTION ELIMINATION... 

The major important organic electrolytes and nonelectrolytes transported by epithelial cells include sugars, amino acids, nucleosides, organic cations, and organic anions. Transport systems have significant implications for the absorption, distribution, elimination, and pharmacokinetic properties of many clinically important drugs. The major epithelial tissues... 

Pharmacology and clinical pharmacology define the desirable and undesirable effects of drugs and xenobiotics whereas pharmacokinetics defines the various processes that are involved in absorption - distribution - elimination of these agents. Needless to say that the former may strongly influence the latter. 

Antagonism is a relatively common phenomenon, and antidotal strategies are often based on this type of interaction. Chemical antagonism is a simple interaction between two chemicals in which the formed complex is less toxic. Functional antagonism occurs when two chemicals have opposing actions on physiology, thus their combined effects counteract each other. Kinetic or dispositional antagonism occurs when the absorption, distribution, elimination, or biotransformation of a chemical is altered by... 

Much of this regulatory zeal was driven by the Delaney Clause, which amended the Food, Drug and Cosmetic Act of 1938. This clause forbids the addition of any amount of animal carcinogen to the food supply. This was originally based on our belief at the time that even one molecule of a carcinogen could cause cancer in humans. This concept was largely influenced by theories of radiation-induced cancer. Thresholds were not allowed. As we discussed, this is no longer considered valid since the processes of absorption, distribution, elimination, metabolism and cellular defense, and repair mechanisms make this possibility far less than remote. However, the United States... 

The bilinear model, in combination with other physicochemical properties (Eq. (30)) [24,62], was the first mathematical expression to describe nonlinear lipophilicity-activity relationships, precisely and in a flexible manner. Besides pharmacokinetic properties, such as absorption, distribution, elimination, and permeation of the... 

Pharmacokinetics is the study of how the body affects an adiriinistered dmg. It measures the kinetic relationships between the absorption, distribution, metaboHsm, and excretion of a dmg. To be a safe and effective dmg product, the dmg must reach the desired site of therapeutic activity and exist there for the desired time period in the concentration needed to achieve the desired effect. Too Htde of the dmg at such sites yields no positive effect ( MTC) leads to toxicity (see Fig. 1). For intravenous adininistration there is no absorption factor. Total body elimination includes both metabohc processing and excretion. 

In cases of all but intravenous adininistration, dosage forms must make the active moiety available for absorption, ie, for dmg release. This influences the bioavailabiUty and the dmg s pharmacokinetic profile. Ideally the dmg is made available to the blood for distribution and elimination at a rate equal to those processes. Through technological developments dmg product design can achieve release, absorption, and elimination rates resulting in durations of activity of 8—12 hours, ie, prolonged action/controlled release dmg products (21,22). Such products improve the compliance rate of dmg usage by patients. 

The absorption, distribution, and accumulation of lead in the human body may be represented by a three-part model (6). The first part consists of red blood cells, which move the lead to the other two parts, soft tissue and bone. The blood cells and soft tissue, represented by the liver and kidney, constitute the mobile part of the lead body burden, which can fluctuate depending on the length of exposure to the pollutant. Lead accumulation over a long period of time occurs in the bones, which store up to 95% of the total body burden. However, the lead in soft tissue represents a potentially greater toxicological hazard and is the more important component of the lead body burden. Lead measured in the urine has been found to be a good index of the amount of mobile lead in the body. The majority of lead is eliminated from the body in the urine and feces, with smaller amounts removed by sweat, hair, and nails. 

Physiologically based toxicokinetic models are nowadays used increasingly for toxicological risk assessment. These models are based on human physiology, and thus take into consideration the actual toxicokinetic processes more accurately than the one- or two-compartment models. In these models, all of the relevant information regarding absorption, distribution, biotransformarion, and elimination of a compound is utilized. The principles of physiologically based pharmaco/ toxicokinetic models are depicted in Fig. 5.41a and h. The... 

Kinetic studies Rats/rniee One day to weeks Absorption, distribution, and elimination... 

Lack of favorable ADME properties (absorption, distribution, metabolism, elimination) can preclude therapeutic use of an otherwise active molecule. The clinical pharmacokinetic parameters of clearance, half-life, volume of distribution, and bioavailability can be used to characterize ADME properties. 

Toxicokinetic—The study of the absorption, distribution and elimination of toxic compounds in the living organism. 

No data were located concerning whether pharmacokinetics of endosulfan in children are different from adults. There are no adequate data to determine whether endosulfan or its metabolites can cross the placenta. Studies in animals addressing these issues would provide valuable information. Although endosulfan has been detected in human milk (Lutter et al. 1998), studies in animals showed very little accumulation of endosulfan residues in breast milk (Gorbach et al. 1968 Indraningsih et al. 1993), which is consistent with the rapid elimination of endosulfan from tissues and subsequent excretion via feces and urine. There are no PBPK models for endosulfan in either adults or children. There is no information to evaluate whether absorption, distribution, metabolism, or excretion of endosulfan in children is different than in adults. 

ADMET absorption, distribution, metabolism, elimination and toxicity... 

Hansch and Leo [13] described the impact of Hpophihdty on pharmacodynamic events in detailed chapters on QSAR studies of proteins and enzymes, of antitumor drugs, of central nervous system agents as well as microbial and pesticide QSAR studies. Furthermore, many reviews document the prime importance of log P as descriptors of absorption, distribution, metabolism, excretion and toxicity (ADMET) properties [5-18]. Increased lipophilicity was shown to correlate with poorer aqueous solubility, increased plasma protein binding, increased storage in tissues, and more rapid metabolism and elimination. Lipophilicity is also a highly important descriptor of blood-brain barrier (BBB) permeability [19, 20]. Last, but not least, lipophilicity plays a dominant role in toxicity prediction [21]. 

FIG. 2 Mechanisms of drug transfer in the cellular layers that line different compartments in the body. These mechanisms regulate drug absorption, distribution, and elimination. The figure illustrates these mechanisms in the intestinal wall. (1) Passive transcellular diffusion across the lipid bilayers, (2) paracellular passive diffusion, (3) efflux by P-glycoprotein, (4) metabolism during drug absorption, (5) active transport, and (6) transcytosis [251]. 

Abou-Donia MB, Suwita E, Nomeir AA. 1990a. Absorption, distribution, and elimination of a single oral dose of [14C]tri-orf/ o-cresyl phosphate in hens. Toxicology 61 13-25. 

Since the body may be viewed as a very complex system of compartments, at first it might appear to be hopeless to try to describe the time course of the drug at the receptor sites in any mathematically rigorous way. The picture is further complicated by the fact that, for many drugs, the locations of the receptor sites are unknown. Fortunately, body compartments are connected by the blood system, and distribution of drugs among the compartments usually occurs much more rapidly than absorption or elimination of the... 

During the past decade, numerous articles reviewing the effects of aging on pharmacokinetic processes (i.e., absorption, distribution, metabolism, and elimination) have been published [115 124h]. An outline of the observations made in these reports is supplied in Table 5. The absorption process is the only process that will be covered in depth in this chapter, as this is the process that can most easily be manipulated through formulation techniques. 

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