Pharmacokinetics distribution kinetics

Kawai R, Mathew D, Tanaka C, Rowland M Physiologically based pharmacokinetics of cyclosporine A extension to tissue distribution kinetics in rats and scale-up to human. J Pharmacol Exp Ther 1998 Nov 287(2) 457-68. 

DIFFUSION OF LIGAND TO RECEPTOR Drug clearance, dosage, PHARMACOKINETICS Drug distribution kinetics, PHARMACOKINETICS Drug excretion rates,... 

Herman, R. A. and P. Veng-Pedersen. 1994. Quantitative structure-pharmacokinetic relationships for systemic drug distribution kinetics not con ned to a congeneric sefi harm. Sci83 423-428. 

Yokogawa K, IshizakiJ, Ohkuma S, Miyamoto K. Influence of lipophilicity and lysosomal accumulation on tissue distribution kinetics of basic drags a physiologically based pharmacokinetic model. Methods Find Exp Clin Pharmacol. 2002 24 81-93. 

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. 

A. Rescigno, Mathematical foundations of linear kinetics. In Pharmacokinetics Mathematical and Statistical Approaches to Metabolism and Distribution of Chemicals and Drugs. (J. Eisenfeld and M. Witten, Eds.), North-Holland, Amsterdam, 1988. 

Ethnic differences have been shown to influence response to psychotropic medications. Much of the focus on the explanation for such differences has been on drug-metabolizing (CYP) enzymes of the liver and their sway over pharmacokinetic factors. It is now well recognized that differences in the distribution of polymorphic variants of CYP enzymes exist between different ethnic groups. However, within ethnic groups there are considerable inter-individual variations in drug kinetics, which may not be accounted for solely by genetic variation. Responses to pharmacotherapy are multifaceted and involve the interaction of environmental and... 

Nonetheless the approach can provide - both routinely and rapidly - large amounts of pharmacokinetic or other distribution information on several compounds without significantly increasing the burden on the animals, whilst also minimizing the number of animals used. It is common to include a compound of known pharmacokinetics that acts as a control in each of these studies. This can help in identifying when the co-administered compounds have changed the kinetics. However, such marker compounds will not necessarily highlight problems with compounds that are subject to different clearance mechanisms [35],... 

There is no experimental evidence available to assess whether the toxicokinetics of -hexane differ between children and adults. Experiments in the rat model comparing kinetic parameters in weanling and mature animals after exposure to -hexane would be useful. These experiments should be designed to determine the concentration-time dependence (area under the curve) for blood levels of the neurotoxic /7-hcxane metabolite 2,5-hexanedione. w-Hcxanc and its metabolites cross the placenta in the rat (Bus et al. 1979) however, no preferential distribution to the fetus was observed. -Hexane has been detected, but not quantified, in human breast milk (Pellizzari et al. 1982), and a milk/blood partition coefficient of 2.10 has been determined experimentally in humans (Fisher et al. 1997). However, no pharmacokinetic experiments are available to confirm that -hexane or its metabolites are actually transferred to breast milk. Based on studies in humans, it appears unlikely that significant amounts of -hexane would be stored in human tissues at likely levels of exposure, so it is unlikely that maternal stores would be released upon pregnancy or lactation. A PBPK model is available for the transfer of M-hcxanc from milk to a nursing infant (Fisher et al. 1997) the model predicted that -hcxane intake by a nursing infant whose mother was exposed to 50 ppm at work would be well below the EPA advisory level for a 10-kg infant. However, this model cannot be validated without data on -hexane content in milk under known exposure conditions. 

For a drug to interact with a target, it has to be present in sufficient concentration in the fluid medium surrounding the cells with receptors. Pharmacokinetics (PK) is the study of the kinetics of absorption, distribution, metabolism, and excretion (ADME) of drugs. It analyzes the way the human body deals with a drug after it has been administered, and the transportation of the drug to the specihc site for drug-receptor interaction. For example, a person has a headache and takes an aspirin to abate the pain. How does the aspirin travel from our mouth to reach the site in the brain where the headache is and act to reduce the pain ... 

Limited data are available on the pharmacokinetics of arecoline. Intravenously administered arecoline in subjects with Alzheimer s disease shows variation in the optimal dose (between 4 and 16 mg/day) due to differing plasma kinetics (Asthana et al. 1996). The mean plasma half-lives for these doses were 0.95 0.54 and 9.3 4.5 minutes, respectively. However, the mean plasma concentrations that optimized cognitive effects were 0.31 0.14 ng/ml. Drug clearance was 13.6 5.8 L/min and the volume of distribution was 205 170 L. 

The pharmacokinetics of ondansetron in man have been determined in healthy volunteers after single and repeat doses [84]. The clinical pharmacokinetics (Table 7.8) showed many similarities with the kinetics in animals, but also some important differences. Elimination is rapid, but less so than in animals. The volume of distribution is similar in animals and man. As in animals, the clearance of ondansetron in man is predominantly by metabolism. However, metabolic clearance in man is considerably lower than in animals, resulting in a lower first-pass metabolism and a significantly greater oral bioavailability of 60 %. Steady-state concentrations of ondansetron are consistent with the single-dose kinetics of the compound and show no evidence of significant accumulation. 

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. 

The pharmacokinetic information that can be obtained from the first study in man is dependent on the route of administration. When a drug is given intravenously, its bioavailabihty is 100%, and clearance and volume of distribution can be obtained in addition to half-life. Over a range of doses it can be established whether the area under the plasma concentration-time curve (AUC) increases in proportion to the dose and hence whether the kinetic parameters are independent of dose (see Figure 4.1). When a drug is administered orally, the half-life can still be determined, but only the apparent volume of distribution and clearance can be calculated because bioavailability is unknown. However, if the maximum concentration (Cmax) and AUC increase proportionately with dose, and the half-life is constant, it can usually be assumed that clearance is independent of dose. If, on the other hand, the AUC does not increase in proportion to the dose, this could be the result of a change in bioavailability, clearance or both. 

Laplace transformation is particularly useful in pharmacokinetics where a number of series first-order reactions are used to model the kinetics of drug absorption, distribution, metabolism, and excretion. Likewise, the relaxation kinetics of certain multistep chemical and physical processes are well suited for the use of Laplace transforms. 

Pharmacokinetics In healthy adults treated with IV doses of iron sucrose, its iron component exhibits first order kinetics with an elimination half-life of 6 hours, total clearance of 1.2 L/h, non-steady-state apparent volume of distribution of 10 L, and steady-state apparent volume of distribution of 7.9 L. 

Studies of dmg absorption, distribution and elimination comprise what is referred to as pharmacokinetics. By contrast, the concentration of a pharmaceutical compound at the site(s) of action in relation to the magnitude of its effect(s) is referred to as pharmacodynamics. Both pharmacokinetics and pharmacodynamics have their roots in physiology, chemical kinetics, biochemistry, and pharmacology. They seek to provide a mathematical basis of the absorption, distribution, metabolisms, and... 

Pharmacokinetics and pharmacodynamics form the two major branches of pharmacoiogy. Pharmacokinetics is the study of drug disposition and deais with the processes of absorption, distribution, metaboiism and eiimination. Pharmacodynamics is concerned with the reiationship between the concentration of a drug and its effect. Put another way, pharmacodynamics is what a drug does to the body whiie pharmacokinetics is what the body does to a drug. This chapter wiii cover the generai principies reiating to these processes, and deveiop some of the principies that describe their kinetics and dynamics. 

Pharmacologic factors include (1) the kinetics of absorption, distribution, and elimination (2) the ability of the drug to be delivered to the site of infection (3) the potential toxicity of an agent and (4) pharmacokinetic or pharmacodynamic interactions with other drugs. 

Pharmacokinetic studies of intravenously administered indomethacin in cattle showed a wide extravascular distribution as suggested by the high volume of distribution and the long elimination half-life observed (99). Similar kinetic behavior of indomethacin was noticed after intramuscular administration in sheep (100). These results suggested that indomethacin could induce high residue levels in tissues. 

Another model, which is increasingly being used, is the physiologically based pharmacokinetic model. This uses data on the absorption, distribution, metabolism, tissue sequestration, kinetics, elimination, and mechanism to determine the target dose used for the extrapolation, but it requires extensive data. 

Pharmacokinetics is the science that describes the movement of a dmg in the body (Jang et al., 2001). In other words, PK is concerned with the time course of a dmg s concentration in the body, mainly in the blood (plasma). The PK parameters are discussed in Chapter 2. Four separate but somewhat interrelated processes influence a drag s movement in the body absorption (A), distribution (D), metabolism (M), and excretion (E). These four major components which influence a drag s level, its kinetics of exposure to tissues, and its performance as a dmg are described in the following ... 

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