Absorption, distribution, and excretion of drugs

Whether an agent is given by mouth or injected, it must usually traverse one or several semi-permeable membranes before the required receptor is encountered. For example, an antimalarial, such as chloroquine (10,28) given by mouth, must penetrate the barrier that lies between the gastrointestinal tract and the blood-stream, then the erythrocyte membrane, and finally that of the malarial parasite. On both sides of each membrane the 

These competing effects are shown diagrammatically in Fig. 3.2, which shows how the frequency and size of the dose depend on all these factors, each arrow representing an equilibrium or a steady state (see Section 3.6, below). Sometimes there is an additional complication the drug which 

2 Distribution of a drug or other biologically active substance. The broken vertical lines indicate selective membranes and R stands for a receptor. 

In this picture of distribution (Fig. 3.2), the reversibility of most of the steps should be noted. 

The useful concept of apparent volume of distribution (I ) of a drug is defined  

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It was apparent that the FDA recognized the ability of the pharmaceutical industry to develop chiral assays. With the advent of chiral stationary phases (CSPs) in the early 1980s [8, 9], the tools required to resolve enantiomers were entrenched, thus enabling the researcher the ability to quantify, characterize, and identify stereoisomers. Given these tools, the researcher can assess the pharmacology or toxicology and pharmacokinetic properties of enantiopure drugs for potential interconversion, absorption, distribution, and excretion of the individual enantiomers. 

Figure 5,4 Pharmacokinetics. The absorption distribution and fate of drugs in the body. Routes of administration are shown on the left, excretion in the urine and faeces on the right. Drugs taken orally are absorbed from the stomach and intestine and must first pass through the portal circulation and liver where they may be metabolised. In the plasma much drug is bound to protein and only that which is free can pass through the capillaries and into tissue and organs. To cross the blood brain barrier, however, drugs have to be in an unionised lipid-soluble (lipophilic) form. This is also essential for the absorption of drugs from the intestine and their reabsorption in the kidney tubule. See text for further details...

In addition to phase I and phase II enzymes, equally important is a group of transporter proteins expressed in various tissues, such as the liver, intestine, brain and kidney, which modulate the absorption, distribution and excretion of many drugs. 

Chu I, Villeneuve DC, Secours V, et al. 1979b. The absorption, distribution and excretion of photomirex in the rat. Drug Metab Dispos 7 24-27. 

Differences in clinical effectiveness are partly due to differences in absorption, distribution and excretion of the individual drugs. In general tetracyclines are absorbed irregularly from the gastrointestinal tract and part of the dose remains in the gut and is excreted in the faeces. However this part is able to modify the intestinal flora. Absorption of the more lipophilic tetracyclines, doxycycline and minocycline is higher and can reach 90-100%. The absorption is located in the upper small intestine and is better in the absence of food. Absorption is impaired by chelation with divalent cations. In blood 40-80% of tetracyclines is protein bound. Minocycline reaches very high concentrations in tears and saliva. Tetracyclines are excreted unchanged, in both the urine by passive filtration and in the feces. Tetracyclines are concentrated in the bile via an active... 

Many of the drug monographs contain a new section entitled Disposition in the Body. This section details die absorption, distribution, and excretion of the drug, notes the major metabolites and therapeutic and toxic plasma concentrations, and gives values for pharmacokinetic parameters such as half-life, volume of distribution, clearance, and protein binding. In addition, abstracts from published clinical studies and case histories are included. 

Tetracycline was discovered after a team of workers examined 100000 soil samples from around the world. Tetracycline derivatives include chlor-tetracycline, oxytetracycline, doxycycline and minocycline. The tetracyclines have a broad spectrum of activity they are effective against Grampositive and Gram-negative bacteria, some anaerobes. Chlamydia, Mycoplasma, Ehrlichia and Rickettsia spp. and some protozoa. Their activity against staphylococci is usually limited and they are not active against enterococci. E. coli, Klebsiella, Proteus and Pseudomonas spp. are usually resistant. Doxycycline and minocycline are usually more active in vitro than the other tetracyclines. Differences in the clinical efficacy of the tetracyclines can be attributed to differences in the absorption, distribution and excretion of the individual drugs rather than to differences in bacterial susceptibility. 

In recent years, it has become apparent that transport proteins play a major role in regulating the absorption, distribution, and excretion of several drugs. Briefly, accumulated evidence has demonstrated that P-glycoprotein (P-gp), a transporter that is embedded in several biological membranes including the blood-brain barrier (BBB) and the GIT, plays an important role in the ADME of many drugs. A major function of P-gp is the energy-dependent cellular efflux of... 

Ayrton, A., Morgan, P., Role of transport proteins in drug absorption, distribution and excretion, Xenobiotica 2001, 31, 469-497. 

Kerberle, H. (1971). Physicochemical factors of drugs affecting absorption, distribution and excretion. Acta Pharmacol. Toxicol. 29 (Suppl 3) 30-47. 

Drug metabolism has been recognized as one of the key factors in the discovery of new chemical entities. A lead compound needs to not only interact with the target enzyme/receptor but also remain over a certain threshold concentration at the site of action for a defined period to produce the desired therapeutic effect. Drug metabolism together with absorption, distribution and excretion are among the factors that influence the final time-concentration relationship of drugs and therefore the potential efficacy of the compound [1],... 

The present volume of the series Methods and Principles in Medicinal Chemistry focuses on the impact of pharmacokinetics and metabolism in Drug Design. Pharmacokinetics is the study of the kinetics of absorption, distribution, metabolism, and excretion of drugs and their pharmacologic, therapeutic, or toxic response in animals and man. 

Pharmacokinetics deals with the alterations of the drug by the body which includes absorption, distribution, binding/ storage, biotransformation and excretion of drugs. 

Adamson RH, Davies DS. Comparative aspects of absorption, distribution, metabolism and excretion of drugs. International Encyclopaedia of Pharmacology and Therapeutics, Section 85 (Comparative Pharmacology). Oxford Pergamon Press, 1973 851. 

Chasseaud LF. Processes of absorption, distribution and excretion. In Hathway DE, Brown SS, Chasseaud LF, et al. Foreign Compound Metabolism in Mammals, Vol. 1. London The Chemical Society, 1970. Findlay JWA. The distribution of some commonly used drugs in human breast milk. Drug Metab Rev 1983 14 653. 

Pharmacokinetic principles, which deal with the absorption, distribution, binding, biotrans-formation, and excretion of drugs and their metabolites in the body (Figure 1.1), are the topic of this chapter. 

Chapter 1, on pharmacokinetics, discussed the processes of absorption, binding, distribution, biotransformation, and excretion of drugs. These processes act efficiently to ensure that a sufficient quantity of drugs reach their receptor sites to elicit the desired therapeutic effects. 

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