Drug clearance tests

Abnormal clearance may be anticipated when there is major impairment of the function of the kidney, liver, or heart. Creatinine clearance is a useful quantitative indicator of renal function. Conversely, drug clearance may be a useful indicator of the functional consequences of heart, kidney, or liver failure, often with greater precision than clinical findings or other laboratory tests. For example, when renal function is changing rapidly, estimation of the clearance of aminoglycoside antibiotics may be a more accurate indicator of glomerular filtration than serum creatinine. 

There are no clear markers of liver dysfunction. Standard liver function tests such as rises in alkaline phosphatase and alanine aminotransferase (see Section 11.10.1) are only crude markers of liver function and have not proved useful in characterizing liver function in relation to drug pharmacokinetics. The effect of liver dysfunction on drug clearance is therefore often addressed descriptively rather than quantitatively (see Weeks and Tomlin, 2006, for further discussion). 

Child-Pugh clinical classification scheme (Table 7.5). Serum albumin concentrations were of greatest predictive value for two of the drugs shown in the table. However, this marker was not correlated with the hepatic clearance of lansoprazole, and a combination of all three laboratory tests was better correlated with hepatic clearance of atorvastatin than was serum albumin alone. Serum concentrations of aspartate aminotransferase (AST) or alanine transaminase (ALT) were not correlated with hepatic drug clearance, as might be expected from the fact that these enzymes reflect hepatocellular damage rather than hepatocellular function. 

In a more thorough and balanced evaluation of the in vitro reactive metabolite tests in both human liver microsomes and S9 fractions, Obach et al. found that a panel of safe drugs in the clinic can form as much reactive metabolites as those hepatotoxic drugs, even after corrections for drug clearance parameters.92-93 Obviously, a more balanced and system-based approach to reactive metabolite formation and its clinical implications is needed hence forward. 

Changes in the volume of distribution may have a significant impact on the efficacy, safety, or both of therapy. An unexpectedly low volume of distribution (such as in the dehydrated patient) wiU result in higher, potentially toxic drug concentrations, whereas a larger-than-expected volume of distribution (such as in patients with edema or ascites) will result in low, potentially subtherapeutic concentrations. The most effective methods use measured serum concentrations of the drugs rather than estimations from renal function tests to assess true drug clearance from the body. 

AO has been shown to be responsible for the primary metabolism of several drugs that contain an aromatic nitrogen heterocycle [72,88,159,160]. In general, when drug structures contain aromatic nitrogen heterocycles, a role for AO should be considered in preclinical and in vitro tests. The contribution of this enzyme to drug clearance can be defined by examining metabolism of an NCE by cytosolic preparations and inhibition by either menadione or raloxifene [161, 162], DDIs with AO have not yet been reported in the literature. 

At the present time no simple relationship exists between clinical measurements of liver function and the value of km. Fortunately, kidney function can be measured quantitatively using standard clinical tests, and it is directly related to ke for a number of drugs. Great success has been achieved in using kidney clearance measurements to predict the biological half-lives of a number of drugs. This is best illustrated with a drug that is eliminated exclusively by urinary excretion. 

Lithium is used in the prophylaxis and treatment of mania and in the prophylaxis of bipolar disorders and recurrent depression. Lithium should be stopped 24 hours before major surgery but the normal dose can be continued for minor surgery, with careful monitoring of fluids and electrolytes. After major surgery, renal function is reduced and this may compromise clearance of lithium. Lithium is a drug with a narrow therapeutic index and it should be avoided if possible in patients with renal impairment. Renal function should be tested before initiating treatment. If lithium is given to patients with renal impairment, a reduced dose should be used and serum lithium concentrations should be monitored closely. 

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