View source for 5. Transport of drugs across membranes

Drugs are transported across membranes all the time. They can either diffuse freely across the lipid matrix or they can be carried across the membrane by specific transporters. Let’s look at them.

''Very few drugs travel across membranes by aquaporins and endocytosis, but they’re not that important and I’ll ignore them.''

''You don’t need to know any of the drug examples here for pharmacology 1, however you should know some for the final exam. You probably don’t need to remember the names and types of transporters either, just the different mechanisms.''

== Summary ==

* Transport of drugs across membrane can occur by free diffusion or by the use of transport proteins
* For a drug to diffuse freely across a membrane it must be lipid soluble
* Weak acids and bases can diffuse across membranes in certain environments, depending on the pH
** Weak acids (like aspirin) are more lipophilic in acidic environments
** Weak bases (like amphetamine) are more lipophilic in basic environments
* Fascilitated diffusion is when a transport protein is needed for the drug to diffuse across the membrane
* Active transport is necessary to transport drugs against their concentration gradient. This requires some form of energy
* Primary active transport is when the transport protein uses ATP for the transport
* Secondary active transport is when one protein creates a concentration gradient of a compound, and another protein uses that concentration gradient to transport another compound across the membrane
* Tertiary active transport is when two proteins create concentration gradients, and another protein uses the concentration gradients to transport another compound across the membrane

== Diffusion ==
Diffusion is important for the absorption of most drugs from the <abbr>GI</abbr> tract and kidney, and for their distribution from the blood into the tissues.

Diffusion depends on three things:

* The lipid solubility of the drug – the more lipid soluble (hydrophobic, lipophilic) the easier it can diffuse across the membrane
* The concentration gradient of the drug
* The area across which the diffusion takes place

We’ll only look at what determines the lipid solubility.

The lipid solubility is higher for drugs that have:

* fewer charged groups, like -OH groups.
* more alkyl groups, like methyl or ethyl groups
* more halogen atoms, like fluorine

Many drugs are acids or bases. Acids exist in this equilibrium: AH <-> A– + H+. When they are in the AH does the molecule have no electrical charge, meaning that it is more hydrophobic than when it is in the A– form. The same goes for bases, which are in this equilibrium: B + H+ <-> BH+. 

The pH of the solution and the pKa value of the drug determines how many of the drug molecules that are in the AH form and how many are in the A– form.

You may have heard that acetylsalicylic acid (aspirin) is absorbed in the stomach and not the GI tract. Acetylsalicylic acid is of course an acid. The stomach acid is acidic, so it contains a lot of H+-ions. This pushes the acid equilibrium toward AH, meaning that most of the drug molecules are in the hydrophobic AH form and not the hydrophilic A– form. This makes it easier for the drug to cross the cell membrane of the epithelial cells in the stomach. Aspirin isn’t taken up from the intestines because the pH is much higher there, which pushes the equilibrium toward the A– form, which doesn’t diffuse as easily.

The opposite is true for amphetamine, which is a base. In the stomach acid is there a lot of H+-ions. This pushes the base equilibrium toward the hydrophilic BH+ form, meaning that it isn’t absorbed in the stomach. In the more basic intestine however are most molecules in the B form, so the drug can be absorbed.

== Carrier-mediated transport ==
This type of transport involves transporter proteins.

=== Facilitated diffusion ===
Facilitated diffusion is the same as diffusion, except instead of diffusion directly across the membrane will the drug diffuse through a transporter protein, which acts like a “bridge” or “gate” through the membrane. This is important for hydrophilic molecules that can’t diffuse across the cell membrane itself.

The GLUT transporters are the best-known example for facilitated diffusion. Glucose flows down the concentration gradient through these proteins.

Equilibrative nucleoside transporter (ENT) is a transporter that allows nucleosides and nucleoside analogues to diffuse through. Many drugs are nucleoside analogues, especially antivirals and anticancer drugs, and these drugs enter the cells through this transporter.

Amino acid transporters don’t just transport amino acids but also amino acid derivatives and drugs that resemble amino acids, like DOPA and methyldopa.

=== Active transport ===
Active transport flows against the concentration gradient. We have primary, secondary and tertiary types.

Primary active transport involves a protein that uses ATP to transport molecules across the cell membrane. The most important type here are the ABC transporters, which may have given you headaches during biochemistry 2. Multi-drug-resistant transport proteins (MDR family), human multidrug resistant protein (MRP family) and breast cancer resistant protein (BCRP) are all ABC transporters that transport drugs out of cells, like out of enterocytes into the GI lumen, out of hepatocytes into the bile, out of tubular cells into the filtrate, and out of the blood brain barrier into the blood.

The drug substrates of the MDR family are large basic or neutral molecules. MDR1 is also called P-glycoprotein (Pgp). Pgp is important in keeping drugs out of the brain by pumping them from the endothelial cells back into the blood.

Many drugs are substrates for Pgp. Appearently they like to ask some examples in the pharma final. Learn some of these:

* Verapamil
* Nifedipine
* Vinblastine
* Doxorubicin
* Dexamethasone
* Protease inhibitors
* Tacrolimus
* Fexofenadine
* .. and many more

Secondary active transport involves two proteins where one of the proteins create a Na+ gradient that the other protein uses to carry the drug across the membrane. A familiar example may be SGLT, the sodium-dependent glucose transporters, that transport glucose across membranes in enterocytes and tubular cells.

Many types exist, but if you’ve already read through topic 17 have you already read about neuronal monoamine transporters (NET), also called uptake-1. Other examples include CNT, SNBT, SMCT, NTCP, NIS and EEAT.

Another type of secondary active transport exists. This type does not use a Na+ gradient but instead the membrane potential itself. This means that they are dependent on the Na+/K+-ATPase. Organic cation transporters (OCT transporters) use this mechanism to transport organic cations from the blood into cells. This includes many drugs.

Tertiary active transport involves three proteins. The first protein is the Na+/K+– ATPase, which generates the membrane potential for the second protein, for example a Na+/α-ketoglutarate exchanger. This creates an α-ketoglutarate gradient, that the third protein uses as the driving force to transport molecules across the membrane. It’s basically secondary active transport, just with another protein.

Organic anion transporters (OAT transporters) use this mechanism with the α-ketoglutarate gradient. OAT1 is found in the proximal tubule cells and mediates the reabsorption of many drugs that are organic acids.

Organic anion-transporting polypeptides (OATP transporters) use the same mechanism, but with glutathione instead of α-ketoglutarate. They’re found in hepatocytes, proximal tubules and enterocytes. They transport into cells organic acids, organic bases and neutral compounds, despite their name.

The next group of transporters use H+ instead of α-ketoglutarate, so it’s driven by both Na+ and H+ gradients. This group includes peptide transporter (PEPT), proton-coupled folate transporter (PCFT) and divalent metal transporter (DMT). PEPT are involved in absorption of peptides and peptide drugs from the intestine. PCFT are involved in the absorption of folate, heme and methotrexate. DMT is known from biochemistry 2 and is involved in absorption of Fe2+ from the intestine.

The last group of transporters use tertiary transport to pump drugs out of cells instead of into them. These also use Na+ and H+ and are called multidrug and toxin extrusion transporter (MATE). They’re involved in drug excretion by tubular cells into urine, by hepatocytes into bile, and from placenta into maternal blood.
[[Category:Pharmacology 1]]