3.3. Elimination of Drug from the Body
3.3.1. Renal excretion
The most important route of excretion for most substances is the through the kidneys, known as renal excretion. There are three processes, filtration, reabsorption and secretion, and they all take place in different parts of the kidney. The main structure in the kidney that performs these tasks is the nephron, as shown in class notes page 16.
A single kidney contains over a million nephrons. The blood flow into the kidney is around 1.2L/min, or 25% of cardiac output. This contains about 650 ml of liquid, of which 130 ml is filtered out and roughly 128 mL is reabsorbed. In a day roughly 1.5L is excreted. The artery entering the kidney divides up into a ball of fine capillaries in the top of each nephron, forming the glomerulus. The high pressure created in these small capillaries causes a large amount of plasma to be filtered out and pass into the proximal tubule. It is in this tubule that water and salt are reabsorbed, but any drug that has passed along with the plasma is not. There is also active secretion of drugs from the plasma in the capillaries around the tubule. The rest of the nephron is involved with salt, glucose and water reabsorption, and acidification of the urine. In diabetes the active reabsorption mechanism for glucose may get saturated, resulting is glucose excretion. It was in fact the observation that flies settled on the sweet urine samples from diabetics that first alerted physicians to this symptom.
3.3.2. Liver Metabolism
The liver affects drug elimination in two ways. As mentioned previously, some drugs are extensively metabolized, or broken down by the liver in the first pass effect which is the result of the physiological fact that all blood supply from most of the GI tract drains directly into the liver. The part of the liver where most of the drug metabolism takes place is known as the microsomal fraction. It is this fraction that is rich in the degradative enzymes. But the liver also excretes some drugs into the bile, and this bile is excreted into the duodenum by an active transport mechanism. If the drug is then reabsorbed from the gut in an active form, it will enter the circulation again. This is called the enterohepatic circulation and is responsible for prolonged plasma drug levels for drugs such as the heart drug digoxin.
3.3.3. Degradation in Plasma
Although the liver is probably the main area of drug metabolism, there are also many enzymes circulating in the blood which break down drugs, especially proteins. Often, too, drugs bind with proteins in the blood, and this can effect their metabolism and excretion. Bilirubin is an example of a compound that binds to serum albumin. In new born babies the liver often has a hard time breaking this plasma conjugate down, and it is deposited in the skin and eyes, giving the yellow appearance that is typical of a jaundiced baby. When a newborn is placed under controlled UV lights, the radiation is sufficient to change the shape of the bilirubin so that it can no longer bind to the protein, and it is much easier to excrete.
3.3.4. Minor Routes
As well as the main areas of kidney and liver, there are many other minor routes of removal such as the sweat, in saliva and in tears.