Renal clearance, equation

Digoxin is not extensively metabolized in humans almost two thirds is excreted unchanged by the kidneys. Its renal clearance is proportional to creatinine clearance and the half-life is 36-40 hours in patients with normal renal function. Equations and nomograms are available for adjusting digoxin dosage in patients with renal impairment. 

From either a Cp or In Cp versus time plot, one feature is immediately clear the drug concentration drops over time. This process is called elimination and is determined by clearance (CL). Clearance is the process of removal of drug from the bloodstream. As was discussed in Chapter 3, clearance occurs primarily either through filtration of a drug by the kidneys (renal clearance, CLR) or metabolism of a drug in the liver by the action of enzymes (hepatic clearance, CLH). Other clearance processes are possible, but CLR and CLh normally comprise the large majority of total clearance (CLy or simply CL) (Equation 7.6). 

The extent of protein binding in the plasma or tissues controls the volume of distribution and affects both hepatic and renal clearance. The volume of distribution (V) depends on the fraction unbound in plasma (/u), the fraction unbound in tissue (/ut), the volume of tissue (Vt), and the volume of plasma (Up) by the equation ... 

It is apparent from QSAR 1.106 and 1.107, that the hydrophobicrequirements of the substrates vary considerably. As expected, renal clearance is enhanced in the case of hydrophilic drugs, whereas nonrenal clearance shows a strong dependency on hydrophobic-ity. Note that QSAR 1.107 is stretching the limits of the bilinear model with only 10 data points The 95% confidence intervals are also large but, nevertheless, the equations serve to emphasize the difference in clearance mechanisms that are clearly linked to hydrophobicity. 

This dilemma is best avoided by calculating dialysis clearance using an equation that is analogous to the equation used to determine renal clearance ... 

Hepatic clearance (CLh) may be defined as the volume of blood perfusing the liver that is cleared of drug per unit time. Usually, hepatic clearance is equated with nonrenal clearance and is calculated as total body clearance (CLe) minus renal clearance (CLr) ... 

It can be seen from Equation 7.11 that oral doses of nonrestrictively metabolized drugs should not need to be adjusted in response to changes in hepatic blood flow. Equation 7.11 also forms the basis for using AUCoral measurements to calculate so-called oral clearance" as an estimate of fuCLint. However, if renal excretion contributes to drug elimination, it will reduce AUCorai and lead to over estimation of fuCLinf unless the contribution of renal clearance is accounted for (2). 

Estimation of creatinine clearance in vegetarians is controversial. Some clinicians advocate use of the 24-hour creatinine clearance in these patients since this method is based on the renal clearance of creatinine. The six-variable Modification of Diet in Renal Disease (MDRD) study equation (see below), which incorporates nutritional parameters such as BUN and albumin, has been suggested as an alternative approach. 

Assuming that the renal clearance of BSP is independent of the plasma concentration and that the plasma concentration after a standard dose falls exponentially over the period of excretion into the urine with a decay constant a, the amount of BSP (U) excreted by the kidney during the time t is given by equation... 

The renal clearance (CLj can then be calculated from Equation (10.59) as... 

These equations contain the usual input-output terms of compartmental mass balances and also a simple first-order renal clearance, which is close to inulin clearance for MTX. The Ri are tissue-to-plasma distribution ratios to account for protein binding. The volumes V, and flows, Q, are known from recorded anatomy and physiology. Other parameters are defined as follows kK, renal clearance kL, saturable rate of drug transport into bile KLy saturation constant for bile transport ko, saturable rate of intestinal absorption Kq, saturation constant for intestinal absorption , nonsaturable rate of intestinal absorption kF, reciprocal of nominal transit time in small intestine. 

Conventionally, renal clearance has been equated to urinary clearance. In this case, the amount of the plasma solute excreted in urine per minute is given by the product of urine flow V (in ml/min) and the concentration of the solute in urine (U). If P denotes the steady 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. 

O Equations to estimate creatinine clearance that incorporate a single creatinine concentration (e.g., Cockcroft-Gault) may underestimate or overestimate kidney function depending on whether acute renal failure is worsening or resolving. 

Drugs can be cleared from the body by metabolism as well as renal excretion, and when this occurs it is not possible to measure directly the amount cleared by metabolism. However, the total clearance rate (TCR), or total body clearance, of the drug can be calculated from its pharmacokinetic parameters using the following equation ... 

Although determination of creatinine clearance rate is a standard clinical procedure, it is difficult to carry out mainly because accurate collection of total urine output over a 24-hour period is required. It can never be certain that this requirement has been met. Since creatinine is produced continuously in muscle and is cleared by the kidney, renal failure is characterized by elevated serum creatinine levels. The degree of elevation is directly related to the degree of renal failure—if it is assumed that the production of creatinine in the muscle mass is constant and that renal function is stable. When these assumptions are valid, there is a direct relationship between serum creatinine level and kanamycin half-life, as shown in Fig. 9. The equation of the line in Fig. 9 is... 

The decrease of renal function with age is independent of the decrease in creatinine production. Because of the difficulty of obtaining complete urine collections, creatinine clearance calculated in this way is at least as reliable as estimates based on urine collections. Fat-free mass (equation [14]) should be used for obese patients, and correction should be made for muscle wasting in severely ill patients. 

Nguyen MK, Kurtz I (2005) Derivation of a new formula for calculating urinary electrolyte-free water clearance based on the Edelman equation. Am J Physiol Renal Physiol 288 F1-F7... 

The most accurate ways in which to estimate renal function currently used in the UK are EDTA clearance and 24-hour urine collection. However these measurements are not always considered necessary and renal function may be estimated by one of a number of equations in use. 

These equations make a number of assumptions and may be used to estimate Mrs RP s renal function this is necessary as toxicity from capecitabine can be increased in individuals with renal impairment (creatinine clearance <50 mL/min). 

From the standpoint of clinical pharmacology/ the utility of using the Cockcroft and Gault equation/ or other methods/ to estimate creatinine clearance stems from the fact that these estimates can alert healthcare workers to the presence of impaired renal function in patients whose creatinine formation rate is reduced. As discussed in Chapter 5, creatinine clearance estimates also can be used to guide dose adjustment in these patients. 

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