Excretion pharmacokinetics

This chapter will review some of the important methods for carrying out in vivo absorption and bioavailability studies, as well as attempt to provide an overview of how the information may be used in the drug discovery process. The chapter is aimed at medicinal chemists and thus will focus on the use of animals in discovery phase absorption, distribution, metabolism, and excretion/pharmacokinetic (ADME/PK) studies, rather than the design of studies that are for regulatory submission, or part of a development safety package. 

Lees P, Taylor J B, Maitho T E et al 1987b Metabolism, excretion, pharmacokinetics and tissue residues of phenylbutazone In the horse. Cornell Veterinarian 77 192-211... 

See also Absorption Distribution Excretion Pharmacokinetics/ oxicokinetics. 

ADME/PK = adsorption, distribution, metabolism and excretion / pharmacokinetic IR = infrared spectroscopy PDA = photodiode array detector NMR = nuclear magnetic resonance ELSD = evaporative light scattering detector ECD = electrochemical detector. 

Pharmacology is the study of the effects of chemicals and the mechanism of these effects on living organisms (pharmacodynamics), and the effects of the living organisms on the chemicals including absorption, distribution, metabolism, and excretion (pharmacokinetics). 

NMR spectroscopy is a powerful tool for chemistry and structural biology, especially when NMR is applied to study protein-ligand interactions. In the drug discovery process, NMR is used to study whether a compound binds to a protein up to the determination of the full three-dimensional structure of the complex.Rational drug discovery requires an early appraisal of all factors impacting on the likely success of a drug candidate in the subsequent preclinical, clinical and commercial phases of dug development. Tlie study of absorption, distribution, metabohsm and excretion/pharmacokinetics (ADME/PK) has de-... 

Drug interactions occur when the presence of one drug affects the activity of another. This may occur either because both drugs act through the same pathway(s) - these are called pharmacodynamic interactions - or through effects on absorption, distribution, metabolism or excretion - pharmacokinetic interactions. The result may be an adverse reaction or modified effectiveness. Some specific examples are given below ... 

The time dependency of the activity/mode of interaction changes among test compounds in relation to the time of experimental observation. Differences in the mode of degradation/excretion/pharmacokinetics occur. 

Prakash C, O Donnell J, Khojesteh C. Excretion, pharmacokinetics and metabolism of the substance P receptor antagonist, CJ-11,974, in humans Identification of polar metabolites by LC/MS/MS and chemical derivatization Drug Metab Dispos 2007b 35 1071-1080. 

For those dmgs that are administered as the racemate, each enantiomer needs to be monitored separately yet simultaneously, since metaboHsm, excretion or clearance maybe radically different for the two enantiomers. Further complicating dmg profiles for chiral dmgs is that often the pharmacodynamics and pharmacokinetics of the racemic dmg is not just the sum of the profiles of the individual enantiomers. 

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. 

Pharmacodynamics is the study of dmg action primarily in terms of dmg stmcture, site of action, and the biochemical and physiological consequences of the dmg action. The availabiUty of a dmg at its site of action is deterrnined by several processes (Fig. 1), including absorption, metaboHsm, distribution, and excretion. These processes constitute the pharmacokinetic aspects of dmg action. The onset, intensity, and duration of dmg action are deterrnined by these factors as well as by the avadabihty of the dmg at its receptor site(s) and the events initiated by receptor activation (see Drug delivery). 

The receptor represents the locus of dmg action. However, the pharmacokinetic processes of absorption (dmg entry), distribution, metaboHsm, and excretion play principal roles in determining in vivo time courses and concentrations of dmgs and thus modify actions initiated at receptors. 

Pharmacokinetic studies are designed to measure quantitatively the rate of uptake and metaboHsm of a material and determine the absorbed dose to determine the distribution of absorbed material and its metaboHtes among body fluids and tissues, and their rate of accumulation and efflux from the tissues and body fluids to determine the routes and relative rates of excretion of test material and metaboHtes and to determine the potential for binding to macromolecular and ceUular stmctures. 

The realization of sensitive bioanalytical methods for measuring dmg and metaboUte concentrations in plasma and other biological fluids (see Automatic INSTRUMENTATION BlosENSORs) and the development of biocompatible polymers that can be tailor made with a wide range of predictable physical properties (see Prosthetic and biomedical devices) have revolutionized the development of pharmaceuticals (qv). Such bioanalytical techniques permit the characterization of pharmacokinetics, ie, the fate of a dmg in the plasma and body as a function of time. The pharmacokinetics of a dmg encompass absorption from the physiological site, distribution to the various compartments of the body, metaboHsm (if any), and excretion from the body (ADME). Clearance is the rate of removal of a dmg from the body and is the sum of all rates of clearance including metaboHsm, elimination, and excretion. 

Studies of the pharmacokinetics of this deHvery system in two animal models have been reported in the Hterature. After iajection of these microspheres at three doses, leuproHde concentrations were sustained for over four weeks foUowing an initial burst (116). The results iadicated that linear pharmacokinetic profiles in absorption, distribution, metaboHsm, and excretion were achieved at doses of 3 to 15 mg/kg using the dmg loaded microspheres in once-a-month repeated injections. 

Absorption, distribution, biotransformation, and excretion of chemical compounds have been discussed as separate phenomena. In reality all these processes occur simultaneously, and are integrated processes, i.e., they all affect each other. In order to understand the movements of chemicals in the body, and for the delineation of the duration of action of a chemical m the organism, it is important to be able to quantify these toxicokinetic phases. For this purpose various models are used, of which the most widely utilized are the one-compartment, two-compartment, and various physiologically based pharmacokinetic models. These models resemble models used in ventilation engineering to characterize air exchange. 

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. 

The pharmacokinetics of azacitidine shows that it is rapidly absorbed after s.c. administration with the peak plasma concentration occurring after 0.5 h. The bioavailability of s.c. azacitidine relative to i.v. azacitidine is approximately 89%. Urinary excretion is the primary route of elimination of azacitidine and its metabolites. The mean elimination half-lives are about 4 h, regardless of i.v. or s.c. administration. 

Interactions resulting from a change in the amount of diug reaching the site of action are called pharmacokinetic interactions (Fig. 1). A co-administered diug can affect any of the processes of absorption, distribution, metabolism, and excretion of the original diug, which are determinants of its pharmacokinetic profile [1-3]. 

Pharmacokinetics refers to activities within the body after a dmg is administered. These activities include absoqrtion, distribution, metabolism, and excretion (ADME). Another pharmacokinetic component is the half-life of the drug. Half-life is a measure of the rate at which drains are removed from the body. 

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