Drugs total body clearance

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 ... 

The total body clearance (CLl[)U ) of the drug in this patient was approximately... 

The answer is e. (Hardman, p 21J The fraction of a drug dose absorbed after oral administration is affected by a wide variety of factors that can strongly influence the peak blood levels and the time to peak blood concentration. The Vd and the total body clearance (Vd x first-order fte) also are important in determining the amount of drug that reaches the target tissue. Only the area under the blood concentration-time curve, however, reflects absorption, distribution, metabolism, and excretion factors it is the most reliable and popular method of evaluating bioavailability... 

If the relationship between CLcr and the kinetic parameters of a drug (i.e., total body clearance [CL] and elimination rate constant [k]) is known, these data should be used to individualize drug therapy (Table 77-3). 

TABLE 77-3 Relationship between Creatinine Clearance and Total-Body Clearance and Terminal Elimination Rate Constant of Selected Drugs ... 

In general, peritoneal dialysis is less effective in removing drugs than hemodialysis and, in fact, does not contribute substantially to total body clearance. 

Because the time function of drug concentration is dependent on the rate at which the drug is cleared from the hypothetical "volume," the AUC function is dependent on total body clearance, CL ... 

Total body clearance ( what goes out ) is given by the apparent volume of distribution (1) x elimination rate constant (A ei) (as we have seen above, is measured in litres, and A ei as a fraction of 1, per unit time. A A ei of 0.1 implies that 1/lOth of a body s load of drug is cleared each hour). Clearance therefore has units of volume per unit time - put in another way it means the fraction of the total Vd cleared of drug per unit time. 

In the clinic, total body clearance of a drug is estimated by taking the ratio of the... 

Disposition In healthy subjects, renal clearance of eptihbatide accounts for approximately 50% of total body clearance, with the majority of the drug excreted in the urine as eptihbatide, deamidated eptihbatide, and other, more polar metabohtes. No major metabohtes have been detected in human plasma. 

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. 

Ethosuximide is completely metabolized, principally by hydroxylation, to inactive metabolites. The drug has a very low total body clearance (0.25 L/kg/d). This corresponds to a half-life of approximately 40 hours, although values from 18 to 72 hours have been reported. 

On the other hand, the volume of disfiibution is significantly increased for orally administered trimethoprim in feverish rabbits compared with their healthy counterparts and absorption is reduced (38). The significance of these changes can be appreciated if one considers that the total body clearance of a drug is... 

In general, a drug is eliminated either unchanged through excretion in the urine and/ or bile or by metabolic conversion into more polar metabohte(s) that can be readily excreted in urine and/or bile. Therefore, total body clearance is a sum of all clearances by various mechanisms and can be expressed mathematically as... 

Cl plasma concentration at time zero fi/2a, distribution half-life f1/2jg, elimination half-life Kej, elimination rate constant from central compartment Ki2/.K2i, transfer rate constant between peripheral and central compartments AUC(o ), total area under plasma drug concentration time curve Vd(area> apparent volume of distribution GB, total body clearance. 

The pharmacokinetic properties of the benzodiazepines in part determine their clinical use. In general, the drugs are well absorbed, widely distributed, and extensively metabolized, with many active metabolites. The rate of distribution of benzodiazepines within the body is different from that of other antiseizure drugs. Diazepam and lorazepam in particular are rapidly and extensively distributed to the tissues, with volumes of distribution between 1 L/kg and 3 L/kg. The onset of action is very rapid. Total body clearances of the parent drug and its metabolites are low, corresponding to half-lives of 20-40 hours. 

An important concept relating to the ability of the body to eliminate a drug is total body clearance (CLt), a term that indicates the rate at which a drug is cleared from the body. It is defined as the volume of plasma from which all drug is removed in a given time (i.e., ml/min) by all routes as expressed in the following equation ... 

For example, if a drug has a total body clearance rate of 100 ml/min and its Vd is 2000 ml, the corresponding Kt would be 0.05 min-1. This value indicates that approximately 5 percent of the remaining drug is eliminated per minute. In a first-order process, the concentration of the remaining chemical is rate limiting. 

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) ... 

What is the underlying cause for these interspecies differences For equal doses, differences in plasma AUC values simply indicate differences in total body clearance. Renal and metabolic elimination processes are the major contributors to total body clearance. When allometric scaling is used as described in Chapter 30, renal clearance tends to exhibit only small differences across species, whereas there are many examples of interspecies differences in metabolism. Further, across many drug categories, metabolism is quantitatively more important than is renal elimination. Therefore, more emphasis on inter species differences in drug metabolism could improve Phase I studies. The next two sections provide specific examples of the impact of monitoring metabolism during early human studies. 

For enantiomeric drugs with low organ clearance, differences in renal or hepatic clearance between stereoisomers may reflect their free fraction in the plasma and not real stereoselectivity of the ability of the organ to remove the free enantiomers (intrinsic clearance) from the plasma. Clearance differences between stereoisomers of verapamil and disopyramide may be a function of plasma protein binding differences. In addition, volumes of distribution as well as concentration ratios of stereoisomers in body fluids to total plasma and blood are influenced by plasma protein binding. For example, the larger volume of distribution and greater total body clearance of R-disopyramide compared to the S isomer may be explained by the lower... 

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