Volume physiological factors

Physiologically based pharmacokinetic (PBPK) models are a special type of PK model that attempts to provide more definition to the model analysis by incorporating physiological factors into the model design, like tissue volumes, blood flow rates, and species-specific enzyme characteristics that can more accurately differentiate the dose-response relationship for a chemical or drug in one species from that of another species. The power of this approach is to be able to perform laboratory studies, both in vitro and in vivo, in common experimental species... 

Absorption from the rectum depends on various physiological factors such as surface area, blood supply, pH, fluid volume, and possible metabolism by microorganisms in the rectum. The rectum is perfused by the inferior and middle rectal arteries, whereas the superior, the middle, and the inferior rectal veins drain the rectum. The latter two are directly connected to the systemic circulation the superior rectal vein drains into the portal system. Drugs absorbed from the lower rectum are carried directly into the systemic circulation, whereas drugs absorbed from the upper rectum are subjected to hepatic first-pass effect. Therefore, a high-clearance drug should be more bioavailable after rectal than oral administration. The volume of fluid in the rectum, the pH of that fluid, and the presence of stool in the rectal vault may affect drug absorption. Because the fluid volume is... 

Figure 12. Two ventilatory states, i.e. 750 ml and 2150 ml tidal volume ( 11 and 32 1 min volumes, respectively), are used to indicate the order and direction of change in compartmental deposition which are induced by such physiological factors. Note the crossover in the P curves at approximately 0.8 pm diameter (AMAD). Reproduced with permission from Task Group on Lung Dynamics (1966). Deposition and retention models for internal dosimetry of the human respiratory tract. Health Physics, 12, 173-207. Lippincott, Williams Wilkins...

The dissolution of a drug in the gut lumen will depend on luminal conditions, e.g., pH of the luminal fluid, volume available, lipids and bile acids and the hydrodynamic conditions produced from the GI peristaltic movements of the luminal content toward the lower bowel. Such physiological factors influence drug dissolution by controlling the different variables in equation 1 that describe the dissolution rate. This is summarised in Table 4.4 adapted from Dress-man et al. (1998). 

The mathematically equivalent expression K=Cl/V is often used in order to emphasize that, when various physiological factors change, clearance and volume of distribution may vary independently of each other, and that K is more correctly viewed as being dependent upon the values of Cl and V. ... 

Physiological factors also determine the effectiveness of dermal preparations. The thickness of the skin varies across the body. The penetration rate is higher when applied on thin skin (e.g. behind the ear, on the eyelid or scrotum) than when applied on thick skin (e.g., palm of the hand, sole of the foot). Comparing the skin of babies and adults, the ratio between body surface (skin) and body volume is larger for babies. In addition, skin absorption in term and in preterm new-boms is increased because their stratum comeum is thinner and the epidermis of children is better perfused and hydrated compared to adults. As a result, the toxicity of active substances applied on a baby s skin can be much higher than on an adult s skin. 

Although blood pressure control follows Ohm s law and seems to be simple, it underlies a complex circuit of interrelated systems. Hence, numerous physiologic systems that have pleiotropic effects and interact in complex fashion have been found to modulate blood pressure. Because of their number and complexity it is beyond the scope of the current account to cover all mechanisms and feedback circuits involved in blood pressure control. Rather, an overview of the clinically most relevant ones is presented. These systems include the heart, the blood vessels, the extracellular volume, the kidneys, the nervous system, a variety of humoral factors, and molecular events at the cellular level. They are intertwined to maintain adequate tissue perfusion and nutrition. Normal blood pressure control can be related to cardiac output and the total peripheral resistance. The stroke volume and the heart rate determine cardiac output. Each cycle of cardiac contraction propels a bolus of about 70 ml blood into the systemic arterial system. As one example of the interaction of these multiple systems, the stroke volume is dependent in part on intravascular volume regulated by the kidneys as well as on myocardial contractility. The latter is, in turn, a complex function involving sympathetic and parasympathetic control of heart rate intrinsic activity of the cardiac conduction system complex membrane transport and cellular events requiring influx of calcium, which lead to myocardial fibre shortening and relaxation and affects the humoral substances (e.g., catecholamines) in stimulation heart rate and myocardial fibre tension. 

Sterility, freedom from pyrogens, and acceptably low level of extraneous particulate matter are critical quality attributes of all injectable products. Additional critical quality attributes depend on the clinical use of the product. For example, for IV, IM, and SC routes, isotonicity and physiological pH (7.4) are always desirable in order to minimize potential irritation upon injection. Other factors may preclude this, however. If the required dose of drug must be administered in a small volume, it may not be feasible to formulate an isotonic solution. Likewise, solubility or stability considerations may preclude formulation at physiological pH. This explains why formulation pH for injectable drugs varies from about pH 2 to about pH 11. 

Dead space. Anatomical dead space is equal to the volume of the conducting airways. This is determined by the physical characteristics of the lungs because, by definition, these airways do not contain alveoli to participate in gas exchange. Alveolar dead space is the volume of air that enters unperfused alveoli. In other words, these alveoli receive airflow but no blood flow with no blood flow to the alveoli, gas exchange cannot take place. Therefore, alveolar dead space is based on functional considerations rather than anatomical factors. Healthy lungs have little or no alveolar dead space. Various pathological conditions, such as low cardiac output, may result in alveolar dead space. The anatomical dead space combined with the alveolar dead space is referred to as physiological dead space ... 

Sodium is freely filtered at the glomerulus. Therefore, any factor that affects GFR will also affect sodium filtration. As discussed previously, GFR is directly related to RBF. In turn, RBF is determined by blood pressure and the resistance of the afferent arteriole (RBF = AP/R). For example, an increase in blood pressure or a decrease in resistance of the afferent arteriole will increase RBF, GFR, and, consequently, filtration of sodium. The amount of sodium reabsorbed from the tubules is physiologically regulated, primarily by aldosterone and, to a lesser extent, by ANP. Aldosterone promotes reabsorption and ANP inhibits it. The alterations in sodium filtration and sodium reabsorption in response to decreased plasma volume are illustrated in Figure 19.6. 

Subsequently, individual data on exposure are converted to dose by using conversion factors (OECD/NEA, 1983). The choice of the appropriate numerical value depends on physiological parameters (e.g. respiratory minute volume) as well as physical characteristics of the inhaled aerosol (e.g. particle size). Mean values range typically from about 5 mSv/WLM (non-occupational exposure) to about 10 mSv/WLM (occupational exposure). 

In biological systems, electron transfer kinetics are determined by many factors of different physical origin. This is especially true in the case of a bimolecular reaction, since the rate expression then involves the formation constant Kf of the transient bimolecular complex as well as the rate of the intracomplex transfer [4]. The elucidation of the factors that influence the value of Kf in redox reactions between two proteins, or between a protein and organic or inorganic complexes, has been the subject of many experimental studies, and some of them are presented in this volume. The complexation step is essential in ensuring specific recognition between physiological partners. However, it is not considered in the present chapter, which deals with the intramolecular or intracomplex steps which are the direct concern of electron transfer theories. 

The most incisive studies of the problem at the molecular level are those from the Felsenfeld laboratory (see, for example. Refs. [75,76]). They have shown that at least under some circumstances, a polymerase can step around a nucleo-some, displacing it in cis, but not causing dissociation. It is not yet clear, however, if this mechanism is physiologically relevant and/or whether it is the only mechanism. There exist results in apparent conflict with this model (i.e.. Ref. [77]). That the in vivo process is certainly more complex than the in vitro models used to date is further indicated by the discovery of elongation factors that markedly increase transcriptional rates and suppress pausing (see, for example, Conaway and Conaway [78]). Thus, the question as to how transcription elongation occurs in a chromatin template remains at least partially unresolved. For a further discussion, see Jackson, this volume, p. 467. 

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