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Pharmacokinetics: Drug elimination and clearance


Content Reviewers:

Yifan Xiao, MD

Pharmacokinetics refers to the movement and modification of medication inside the body.

Or more simply, it’s what the body does to this medication and how it does it.

Alright, so once the medication is administered, it first has to be absorbed into the circulation, then distributed to various tissues throughout the body, metabolized or broken down, and finally, eliminated or excreted in the urine or feces.

You can remember this as ADME- Absorption, Distribution, Metabolism, and Excretion.

Okay, now let’s focus on a process called elimination, which is often confused with the process of excretion.

Elimination is the removal of a medication from the body.

Now this can be accomplished through metabolism, where the medication is broken down into inactive metabolites, or through excretion which is when the intact medication is transported out of the body.

This can happen through a number of ways, but the most common route is through urination.

So, the major function of the kidneys is to clear metabolic waste material and foreign substances, like medications, from the body by filtering the blood.

Now, zooming in on a nephron’s tubule, each one is lined by cells that have two surfaces.

One is the apical surface, which faces the tubular lumen, and the other is the basolateral surface, which faces the peritubular capillaries, which run alongside the nephron.

Alright, so first, certain medications in the circulation can be filtered out with the other metabolic wastes when the blood goes through the glomerulus.

Second, as the filtrate makes its way through the proximal convoluted tubule, certain medications from the peritubular capillaries get secreted into the tubular lumen.

For polar, water-soluble medications, this is mainly done actively through active secretion, meaning that it requires specific carrier proteins on the basolateral membrane of the tubular cells, which uses ATP for energy.

Non- polar, lipid- soluble drugs, on the other hand, are secreted into the proximal tubule via passive diffusion, meaning without requiring any energy.

That’s because they can pass through the cell membranes easily, so they just move down their concentration gradient from the peritubular blood into the tubular lumen.

Now, as the filtrate travels towards the distal convoluted tubule, the level of medication builds up inside the lumen, so its concentration rises higher than the peritubular capillaries.

Now, if the medication is non- polar and lipid- soluble, it may passively diffuse out of the tubular lumen and back into the peritubular circulation.

On the flip side, polar and water-soluble medications can’t cross the membranes of tubular cells, so they get trapped inside the tubular fluid and are eliminated from the body with the urine.

Next, the acidity of the urine will also affect excretion.

Most medications are either weak acids or weak bases, and can exist in both a uncharged, non- polar, lipid- soluble form, as well as a charged, polar, water-soluble form.

The ratio between the two forms is determined by the pH of the urine and by the strength of the weak acid or base, which is mainly shown by the ionization constant pKa.

The pKa is the pH at which concentrations of the uncharged and charged forms equal each other.

So, let’s say we place a weak acid, “HA”, in alkaline urine with a higher pH than the pKa.

Since there’s less H+ ions around, it’s going to give up its own H+ ion and turn into its charged form, “A-”.

Since it’s now polar, it can’t pass back through the tubular cell’s membrane.

On the flip side, let’s put a weak base “B” into acidic urine, with a pH lower than its pKa.

With plenty of H+ ions around, it’s going to grab one of them and turn into its charged form “BH+”, which, once again, cannot be reabsorbed across the tubular cell’s membrane.

In other words, weak acidic medications are trapped in alkaline urine, in contrast to weak basic medications which get trapped in acidic urine.

The practical point in this is that an individual presenting with an overdose of a weak acid, like aspirin, can be given a base, like sodium bicarbonate, which makes the urine alkaline and helps get rid of aspirin.

Likewise, overdose of a weak base, like amphetamines, can be treated by acidifying the urine with ammonium chloride.

Okay, now aside from the kidneys, excretion of medications can also take place through the bile and feces.

So orally administered drugs that do not get absorbed from the gastrointestinal tract are directly passed in feces.

Some drugs that are absorbed in the GI tract enter the enterohepatic circulation to get to the liver.

Here, they bind to bile, which is excreted back into the intestine and then leaves the body through the feces.

Also, many inhaled anesthetics get eliminated by the lungs through the exhaled air.

Aside from these main routes of excretion, small amounts of certain medications can leave the body in the breast milk, sweat, saliva, and tears.

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