Clearance renal physiology

Drug clearance principles are similar to the clearance concepts of renal physiology. Clearance of a drug is the factor that predicts the rate of elimination in relation to the drug concentration ... 

The clinical performance of a hemodialy2er is usually described in terms of clearance, a term having its roots in renal physiology, which is defined as the rate of solute removal divided by the inlet flow concentration as shown in equation 7, where Cl is clearance in ml,/min and all other terms are as defined previously except that, in deference to convention, flow rates are now expressed in minutes rather than seconds and feed side (/) is now synonymous with blood flow on the luminal side. 

Oxalate is excreted primarily by the kidney. Oxalate is freely filtered at the glomerulus, where its concentration is normally 1 5 pM. One of the few physiologic functions of oxalate occurs in the proximal tubule where it plays a role in transcellular reabsorption of chloride (mainly present as sodium chloride). Cl entry across the apical membrane is mediated by Cl /oxalate exchange (oxalate is recycled from the tubular lumen to the cell by oxalate/ sulfate exchange, in parallel with Na /sulfate cotransport) [4]. Early studies of renal oxalate clearance using radio-labeled oxalate showed secretion in almost all subjects studied. More recent studies using direct measurement of serum and urine... 

Beierwaltes WH, Harrison-Bernard LM, Sullivan JC, and DL Mattson (2013). Assessment of renal function clearance, the renal microcirculation, renal blood flow, and metabolic balance. Comprehensive Physiology 3(l) 165-200. 

The drawback of this approach is that it is essentially empirical, and does not allow for differences in metabolic clearance between the species, i.e., it assumes that clearance is proportional to blood flow. This works well for compounds that are highly extracted in the liver, and/or where passive renal clearance is the major pathway [5, 68]. An approach for compounds that are actively secreted into the urine has also been proposed [69], although the precise values of some of the physiological scaling factors have been questioned [70]. 

Assuming the capsular pressures opposing the movement of water out of the blood and into the top of the nephron are constant, the net filtration pressure is due largely to the blood pressure. Any fall in blood pressure can have a dramatic effect on the efficiency of filtration and therefore clearance of waste materials. So important is the pressure within the renal vasculature that the kidney is critical in regulating systemic blood pressure via the renin-angiotensin-aldosterone (RAA) axis, a physiological process which relies on transport mechanisms within the renal tubules. 

Renal clearance of cotinine is much less than the glomerular filtration rate (Benowitz et al. 2008b). Since cotinine is not appreciably protein bound, this indicates extensive tnbnlar reabsorption. Renal clearance of cotinine can be enhanced by np to 50% with extreme urinary acidification. Cotinine excretion is less influenced by urinary pH than nicotine becanse it is less basic and, therefore, is primarily in the unionized form within the physiological pH range. As is the case for nicotine, the rate of excretion of cotinine is influenced by urinary flow rate. Renal excretion of cotinine is a minor route of elimination, averaging about 12% of total clearance. In contrast, 100% of nicotine Ai -oxide and 63% of 3 -hydroxycotinine are excreted unchanged in the urine (Benowitz and Jacob 2001 Park et al. 1993). 

Due to the metabolic stability, low molecular weight and absence of ionization at physiological pH, fluconazole has to rely on renal clearance as its major clearance mechanism. The compound has a log P or D7 4 value of 0.5, which means following filtration at the glomerulus a substantial proportion (80 %) of the compound in the filtrate will undergo tubular reabsorption. The resultant low rate of renal clearance gives fluconazole a 30-h half-life in man and is consequently suitable for once-a-day administration. 

Labeling of iodinated aromatics with radioactive or has proved to be a valuable approach to measure GFR in nuclear medicine. Prominent among these is sodium iothalamate, which is specifically marketed in the US for GFR measurement by the name Glofil . Studies have shown that the clearance of this marker by the glomeruli is reproducible, simple, reliable and accurate, especially in children and those with advanced renal diseases [234]. This marker can also be administered by subcutaneous infusion to obtain GFR values without the need for urine collection [235]. Since very low doses (nanomolar scale) of radioactive aromatics are administered, monitoring of renal function may be achieved without disruption of normal physiologic functions. Concerns over radioactivity and associated handling costs may prevent the use of these compounds for routine GFR measurements. 

An instructive example is the physiological variable serum creatinine. Creatinine is an endogenous metabolite formed from, and thus reflecting, muscle mass. Total body muscle mass is sufficiently constant to render measurement of serum creatinine useful for assessing actual renal function. The serum value of creatinine (R) is namely dependent on the continuous (zero-order) input of creatinine into the blood (A in) and its renal elimination rate, which is a first-order rate process (A out x ) In case of an extensive muscle breakdown, kin will temporarily increase. It may also be permanently low, for example in old age when muscle mass is reduced. Likewise, creatinine clearance may decrease for various reasons, described by a decrease in A out- An increase in creatinine clearance may occur as well, for example following recovery from renal disease. According to pharmacodynamic indirect response models. 

Marked inter-patient variability exists in the pharmacokinetics of intravenous anaesthetics. Factors that can influence drug disposition include the degree of protein binding, the efficiency of the hepatic and renal clearance systems, physiological changes with ageing, disease states, site of operation, body temperature, and drug interactions (premedicants, volatile anaesthetics). 

The molecular weight or size of an optimal delivery system in vivo is imposed by the physiology of circulation and excretion. The lower limit of the molecular weight is about 30 kDa because the microtubular cells in the kidney readily excrete hydrophilic molecules whose molecular weight is 30 kDa or less.23 In fact, this is the major route of elimination for many small-molecule drugs after they are transformed into more hydrophilic metabolites. Therefore, a drug delivery system should have a combined molecular weight of 30 kDa to avoid such a quick renal clearance. 

Boom SP, Meyer I, Wouterse AC, et al. A physiologically based kidney model for the renal clearance of ranitidine and the interaction with cimetidine and probenecid in the dog. Biopharm Drug Dispos 1998 19 199-208. 

In a subsequent step the modeler tries to explain part of the unexplained inter individual variability. Fitted individual parameters (or the variable part expressed by rj) are plotted against physiological parameters like weight or indicators of renal or metabolic functionality. Identified dependencies should enter into the model. For example clearance is very often modeled as depending on the covariate CLCr (creatinine clearance) ... 

Russel FG, Wouterse AC, Van Ginneken CA. 1987. Physiologically based pharmacokinetic model for the renal clearance of salicyluric acid and the interaction with phenolsulfon-phthalein in the dog. Drug Metab Dispos 15 695-701. 

Renal function is an indication of the physiological state of the kidney glomerular filtration rate (GFR) describes the flow rate of Altered fluid through the kidney, while creatinine clearance rate (Ccr) is the volume of blood plasma that is cleared of creatinine per unit time, and is a useful measure for approximating the GFR. Most clinical tests use the plasma concentrations of the waste substances of creatinine and urea, as well as electrolytes, to determine renal function. The nephron is the functional unit of the kidney (Figure 10.1) it consists of two parts ... 

The clearance concept has been used in defining the pharmacokinetics of drugs since the mid-1970s. " The elearanee eoneept is based in physiology, where it is used as a measure of renal funetion (ereatinine elear-ance). Creatinine is formed from muscle breakdown at a constant rate, and thus a constant creatinine concentration in plasma results. The magnitude of this concentration is dependent on the elimination rate of ereatinine and the size of the muscle pool (formation rate). By measuring the plasma concentration and the renal excretion of ereatinine, renal clearance can be estimated and thereby kidney function indicated, as ereatinine is mainly filtered into the urine... 

Clearance and volume of distribution are two separate and independent characteristics of a drug. They are closely correlated with physiologic mechanisms in the organism (thereby the term primary parameters). Clearance defines the body s ability to remove the drug, that is, by metabolism or by renal or biliary excretion. Volume of distribution is a measure of the physical interrelationship between the drug and body constituents, such as binding to plasma proteins or partition into muscle, tissue, or fat. 

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