Pharmacokinetics discussion

The principles of pharmacokinetics (discussed in this chapter) and those of pharmacodynamics (discussed in Chapter 2 Holford Sheiner, 1981) provide a framework for understanding the time course of drug effect. 

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. 

Chapter 10. This involvement of pharmacokinetic discussion throughout the book attests to its central importance in new drug development. 

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. 

The pharmacokinetics of batbitutates have been discussed by Chatney et al. (2001) and Harvey (1985). When used as hypnoticsotantianxiety agents, the barbiturates ate administeted otaUy. As anticonvulsants, they may be used either orally or intravenously, although the lattet toute of administtation may be problematic because these dtugs ate vety alkaline and nectosis and pain oc-cut at the site of injection. 

As discussed above, all ADMET aspects are dependent on each other and should all be considered when making predictions. Integrated analysis of different aspects of drug pharmacokinetic profiles is yet another future trend. Ultimately, drug ADMET properties should be predicted based on an integration of a compilation of in silico models reflecting different aspects of the process. 

Useful discussions reviewing PK model structure [12] and PK correlations [13] and describing applications or PK models [14,15] are recommended. Comprehensive reviews of pharmacokinetic modeling are given by Lin and Lu [16] and Sheiner and Steimer [17]. 

Octanol-water partition (log P) and distribution (log D) coefficients are widely used to make estimates for membrane penetration and permeability, including gastrointestinal absorption [77, 78], BBB crossing [60, 69] and correlations to pharmacokinetic properties [1]. The two major components of lipophilicity are molecular size and H-bonding [57], which each have been discussed above (see Sections 2.5 and 2.6). 

SSRIs are the drugs of choice for PD. All SSRIs have demonstrated effectiveness in controlled trials, with 60% to 80% of patients achieving a panic-free state.28,48,49 With similar efficacy reported and no trials comparing SSRIs with other SSRIs, selection generally is based on pharmacokinetics, drug interactions, side effects, and cost differences (see Chap. 35 for more discussion). The most common side effects of SSRIs include headaches, irritability, nausea and other gastrointestinal complaints, insomnia, sexual dysfunction, increased anxiety, drowsiness, and tremor.49 SSRIs should not be discontinued abruptly to avoid a withdrawal syndrome characterized by dysphoric mood, irritability, and agitation. 

Although EPO deficiency is the primary cause of CKD anemia, iron deficiency is often present, and it is essential to assess and monitor the CKD patient s iron status (NKF-K/DOQI guidelines). Iron stores in patients with CKD should be maintained so that transferrin saturation (TSAT) is greater than 20% and serum ferritin is greater than 100 ng/mL (100 mcg/L or 225 pmol/L). If iron stores are not maintained appropriately, epoetin or darbepoetin will not be effective, and most CKD patients will require iron supplementation. Oral iron therapy can be used, but it is often ineffective, particularly in CKD patients on dialysis. Therefore, intravenous iron therapy is used extensively in these patients. Details of the pharmacology, pharmacokinetics, adverse effects, interactions, dose, and administration of erythropoietin and iron products have been discussed previously. 

The success of any drug delivery system depends upon how it interacts with the biological system to deliver its drug at the optimum rate and at the site where it is needed. This paper discusses some of the considerations that must be made in developing successful drug delivery systems and the opportunities available if a comprehensive assessment is made of the pharmacology, pharmacokinetics, and pharmacodynamics involved. 

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