Drug distribution pharmacokinetic/pharmacodynamic

Although there has been little data generated on the topic, this altered method of delivery to the systemic circulation may have profound effects on the subsequent distribution, pharmacokinetics, and pharmacodynamics of the drug molecule and have an impact on the wider area of drug binding to plasma lipoproteins and the potential effects of lipids on this process. 

As was noted in Chapter 4, pharmacokinetic and pharmacodynamic effects are studied in nonclinical research. These topics are also of critical importance in clinical investigations. A drug s pharmacokinetics and pharmacodynamics are of considerable interest to clinicians who may prescribe the drug to patients once it is approved. Meaningful decisions about a drug s optimal use can only be made with an understanding of the time course of events that occur after the drug s administration, and both pharmacokinetics and pharmacodynamics are concerned with this time course. By consideration of the pharmacokinetic processes of absorption, distribution, metabolism, and excretion (ADME), the... 

Mould, D. R. Defining covariate distribution models for clinical trial simulation. In Kimko, H. C., Duffull, S. B., eds. Simulation for designing clinical trials. A pharmacokinetic-pharmacodynamic modeling perspective. (Drugs and the pharmaceutical sciences, volume 127) Marcel Dekker, New York, 2003. 

The inherent pharmacologic properties of a drug determine its pharmacodynamic effects, and drug absorption, distribution, metabolism, and excretion are determined by the pharmacokinetic effects. The ease with which a drug passes into the systemic circulation and its ability to penetrate the blood-brain, blood-aqueous, or blood-retinal barriers determines the propensity to affect ocular tissues and functions. 

FIGURE 3.6 Compartmental analysis for different terms of volume of distribution. (Adapted from Kwon, Y., Handbook of Essential Pharmacokinetics, Pharmacodynamics and Drug Metabolism for Industrial Scientists, Kluwer Academic/Plenum Publishers, New York, 2001. With permission.) (a) Schematic diagram of two-compartment model for compound disposition. Compound is administrated and eliminated from central compartment (compartment 1) and distributes between central compartment and peripheral compartment (compartment 2). Vj and V2 are the apparent volumes of the central and peripheral compartments, respectively. kI0 is the elimination rate constant, and k12 and k21 are the intercompartmental distribution rate constants, (b) Concentration versus time profiles of plasma (—) and peripheral tissue (—) for two-compartmental disposition after IV bolus injection. C0 is the extrapolated concentration at time zero, used for estimation of V, The time of distributional equilibrium is fss. Ydss is a volume distribution value at fss only. Vj, is the volume of distribution value at and after postdistribution equilibrium, which is influenced by relative rates of distribution and elimination, (c) Time-dependent volume of distribution for the corresponding two-compart-mental disposition. Vt is the starting distribution space and has the smallest value. Volume of distribution increases to Vdss at t,s. Volume of distribution further increases with time to Vp at and after postdistribution equilibrium. Vp is influenced by relative rates of distribution and elimination and is not a pure term for volume of distribution. 

The vast majority of SARMs that have been reported are nonsteroidal. Notable exceptions are a series of Merck patents (see above) and MENT [229]. Thus, it can be expected that many of the pharmacokinetic (what the body does to the drug absorption, distribution, metabolism and excretion) and pharmacodynamic (what the drug does to the body pharmacologic, phenotypic and toxicologic effects) problems inherent to the steroid nucleus may be absent in SARMs. Pharmacokinetic/pharmacodynamic profiles have been published for a number of nonsteroidal SARMs [230]. 

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