Elimination, drug excretion

At t = oo after elimination is complete, the total amount of drug excreted unchanged in urine (Z> ) can be calculated using Eq. (26) as follows ... 

Clearance refers to the elimination of drug from the body. It is defined as the volume of blood which is completely cleared of drug per unit time. The drug can be eliminated via excretion through kidneys, and/or metabolism in liver, or through other routes such as saliva, milk, sweat, etc. The clearance associated with the kidney is called the renal clearance (C1r), and the clearance associated with other routes including metabolism is known as non-renal... 

With the exception of intravenous administration, where a drug is injected directly into the bloodstream, all the routes of administration require the drug to be absorbed before it can enter the bloodstream for distribution to target sites. Metabolism may precede distribution to the site of action, for example, in the case of oral administration. The human body also has a clearance process to eliminate drugs through excretion. We will now consider absorption, distribution, metabolism, and excretion with reference to Fig. 5.5. 

Excretion is the process of eliminating drugs from the body. They may be excreted as metabolites or as unchanged drug. As mentioned above, compounds that are polar and water soluble are more readily eliminated. The major routes of excretion are renal, biliary/fecal, lactational, and pulmonary. 

Buspirone is well absorbed from the gastrointestinal tract, and peak blood levels are achieved in 1 to 1.5 hours the drug is more than 95% bound to plasma proteins. Buspirone is extensively metabolized, with less than 1% of the parent drug excreted into the urine unchanged. At least one of the metabolic products of buspirone is biologically active. The parent drug has an elimination half-life of 4 to 6 hours. 

Although thiotepa is chemically less reactive than the nitrogen mustards, it is thought to act by similar mechanisms. Its oral absorption is erratic. After intravenous injection, the plasma half-life is less than 2 hours. Urinary excretion accounts for 60 to 80% of eliminated drug. 

Methotrexate is well absorbed orally and at usual dosages is 50% bound to plasma proteins. The plasma decay that follows an intravenous injection is triphasic, with a distribution phase, an initial elimination phase, and a prolonged elimination phase. The last phase is thought to reflect slow release of methotrexate from tissues. The major routes of drug excretion are glomerular filtration andl active renal tubular secretion. 

Hexamethylmelamine is readily absorbed after oral administration, with peak plasma levels achieved after 1 hour. The drug is readily metabolized to form a number of demethylated metabolites. Urinary elimination is the primary route of drug excretion. 

A related issue is the patient s ability to metabolize and eliminate drugs adequately. For example, lithium is excreted entirely by the kidneys, and if a patient suffers from significantly impaired renal function, high, potentially toxic levels could develop on standard doses. Although the dose could be adjusted to compensate for the decrease in drug clearance, it might be more appropriate to choose another mood stabilizer such as valproate or carbamazepine, because they are primarily metabolized through the liver. 

Tetracyclines are excreted mainly in bile and urine. Concentrations in bile exceed those in serum tenfold. Some of the drug excreted in bile is reabsorbed from the intestine (enterohepatic circulation) and may contribute to maintenance of serum levels. Ten to 50 percent of various tetracyclines is excreted into the urine, mainly by glomerular filtration. Ten to 40 percent of the drug is excreted in feces. Doxycycline and tigecycline, in contrast to other tetracyclines, are eliminated by nonrenal mechanisms, do not accumulate significantly and require no dosage adjustment in renal failure. 

Excretion is tlie process by which the parent drug and its metabolites are removed from the body fluids before elimination occurs. The most important site of drug excretion is die kidney. Extrarenal sites of excretion include die liver, lung, mammary gland, sweat gland, salivary glands, and intestinal mucosa. 

In species where reabsorption of drugs from the gastrointestinal tract increases the half-life of elimination, salivary secretion represents another important excretion route. The large volume of alkaline saliva produced by ruminants offers the possibility of trapping the acidic drugs. Exhalation of products of drug metabolism, such as carbon dioxide and water, can also account for drug excretion. 

Rofecoxib reaches peak plasma concentrations between 2 to 9 h after oral administration. It is bound 87% to plasma protein and has an elimination half-life of about 17 h. Its main metabolites in the liver are the c/ s-dihydro and trans-dihydro derivatives which are excreted mainly in the urine (72%) with some unchanged drug excreted in the faeces (14%). 

The optimal administration of drugs in clinical practice is facilitated by effective application of the principles of clinical pharmacokinetics (PK) and pharmacodynamics (PD). Relationships between drug levels in the systemic circulation and various body compartments (e.g., tissues and biophase) following drug administration depend on factors governing drug absorption, distribution, elimination, and excretion (ADME). Collectively, the study of the factors that govern the ADME processes is termed pharmacokinetics. 

Disposition in the Body. Readily absorbed after oral administration. Metabolised by oxidation to the 3-hydroxymethyl derivative which is conjugated with sulphate or further metabolised to the 3-carboxy derivative. About 90% of a dose is excreted in the urine in 5 to 6 days, of which 6 to 50% is unchanged drug the 3-hydroxymethyl and 3-carboxy metabolites each account for about 20 to 30% of the excreted material the amount of unchanged drug excreted in the urine appears to be reduced in hypertensive patients about 2% of a dose is eliminated in the faeces. 

Compounds that enhance bile production stimulate biliary excretion of drugs normally eliminated by this route, whereas biliary excretion of drugs will be decreased by compounds that decrease bile flow or by pathophysiologic conditions that cause cholestasis (8). Route of administration may also influence the extent of drug excretion into bile. Oral administration may cause a drug to be extracted by the liver and excreted into bile to a greater degree than if the intravenous route were used. 

Renal excretion 1 Clearance and half-life of renally eliminated drugs... 

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