Blood-flow-normalized clearance

Liver Blood Flow and Liver Blood Flow Normalized Clearance in Common Species... 

CL can be easily converted to a more meaningful number called blood-flow-normalized CL that reflects the elimination efficiency. This is related to the notion that CL is a flow that takes a compound out of the systemic circulation. For example, the maximum liver clearance should not exceed the liver blood flow, since the clearing rate cannot exceed the delivery rate. The value of liver clearance is therefore more meaningful when compared to its blood flow as expressed by the extraction ratio E = CLh/gh, where CLh is hepatic clearance and Qh is hepatic blood flow. Typically, the liver is the major organ for elimination. Liver has a relatively... 

A substance that fulfills these criteria is para-aminohippuric acid (PAH). All of the PAH not filtered at the glomerulus is secreted by the proximal tubule. The net effect is that all of the plasma flowing through the nephrons is completely cleared of PAH. It is important to note that about 10 to 15% of the total renal plasma flow supplies regions of the kidneys that are not involved with filtration or secretion. Consequently, this plasma cannot be cleared of PAH. Therefore, the plasma clearance of PAH provides a measurement of the effective renal plasma flow, that is, the volume of plasma that actually flows through the nephrons. The ERPF is normally about 625 ml/ min. (This value is based on a renal blood flow of about 1.1 1/min and a hematocrit of about 42.)... 

Cardiac index and blood pressure must be sufficient to ensure adequate organ perfusion, as assessed by alert mental status, creatinine clearance sufficient to prevent metabolic azotemic complications, hepatic function adequate to maintain synthetic and excretory functions, a stable heart rate and rhythm, absence of ongoing myocardial ischemia or infarction, skeletal muscle and skin blood flow sufficient to prevent ischemic injury, and normal arterial pH (7.34 to 7.47) with a normal serum lactate concentration. These goals are most often achieved with a cardiac index greater than 2.2 L/min/m2, a mean arterial blood pressure greater than 60 mm Hg, and PAOP of 25 mm Hg or greater. 

In patients with heart failure, lidocaine s volume of distribution and total body clearance may both be decreased. Thus, both loading and maintenance doses should be decreased. Since these effects counterbalance each other, the half-life may not be increased as much as predicted from clearance changes alone. In patients with liver disease, plasma clearance is markedly reduced and the volume of distribution is often increased the elimination half-life in such cases may be increased threefold or more. In liver disease, the maintenance dose should be decreased, but usual loading doses can be given. Elimination half-life determines the time to steady state. Thus, although steady-state concentrations may be achieved in 8-10 hours in normal patients and patients with heart failure, 24-36 hours may be required in those with liver disease. Drugs that decrease liver blood flow (eg, propranolol, cimetidine) reduce lidocaine clearance and so increase the risk of toxicity unless infusion rates are decreased. With infusions lasting more than 24 hours, clearance falls and plasma concentrations rise. Renal disease has no major effect on lidocaine disposition. 

The calculation of clearance using this equation is illustrated by the following example. Aspirin is metabolized primarily in the liver. Normal hepatic blood flow (Q) equals 1500 mL/min. If the blood entering the liver contains 200 fxg/mL of aspirin (Ci) and the blood leaving the liver contains 134 fxg/mL (Co), hepatic clearance of aspirin is calculated as follows ... 

Fig. 7. Renal plasma clearance of 125I-cystatin C (Ccy) compared to that of 51 Cr-EDTA (Cq-—edta) in rats with normal glomerular filtration ( ), and in rats with renal blood flow reduced to 25-50% of control by constricting the aorta above the renal arteries (o). The clearance measurements were completed 2.5-6.0 min after tracer injection. Ccy = 0.944 x Ccr-EDTA f = 0.989.

Elimination. Renal blood flow, glomerular filtration and tubular secretion decrease with age above 55 years, a decline that is not signalled by raised serum creatinine concentration because production of this metabolite is diminished by the age-associated diminution of muscle mass. Indeed, in the elderly, serum creatinine may be within the concentration range for normal young adults even when the creatinine clearance is 50 ml/min (compared to 127 ml/min in adult male). Particular risk of adverse effects arises with drugs that are eliminated mainly by the kidney and that have a small therapeutic ratio, e.g. aminoglycosides, chlorpropamide, digoxin, lithium. 

Question Dmg A has a volume of distribution of 500 L 10% is excreted unchanged with a total clearance of 80 L/hour. Liver blood flow is normal (90 L/hour). What... 

Oral clearance is a common term used in the pharmaceutical industry to describe the apparent CL of an orally dosed compound, expressed as CL// = Dose/AUC. Oral clearance is the reciprocal of dose-normalized AUC. Oral clearance reflects the overall exposure efficiency, without differentiating the efficiency of compound delivery or elimination, while IV clearance only reflects the exposure efficiency caused by elimination. Oral clearance is equal or higher than IV clearance. When bioavailability is high, oral clearance is very close to IV clearance. If the bioavailability is low, either due to low absorption or high first-pass effect, oral clearance can be much higher than IV clearance. High oral clearance indicates very low exposure efficiency. When absorption is complete (Fa% = 100), oral CL is actually the intrinsic hepatic clearance for a compound when hepatic metabolism is the major elimination route. Neither oral clearance nor intrinsic CL is limited by the blood flow. 

SembH. 1966. Plasma clearance of Sr85 by bone An attempt to study the rate of blood flow through normal and immobilized bone in dogs. Acta Soc Med Ups 71(5) 227-236. 

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