Science Education

The Multiplicious Identities of Drugs

Imagine you are suffering from a form of leukemia and require treatment. Your doctor offers you a choice between the following drugs:

1. Ambochlorin
2. 4-[bis(2-chlorethyl)amino]benzenebutanoic acid
3. Leukeran
4. Chlorambucil

Knowing nothing about their respective side effects, efficacies, modes of delivery, or costs (some may be covered by the government, some by private insurances, some not at all), which one would you, as a patient, be tempted by? Which of these drugs sounds the most appropriate?

Some might be tempted by number 2, with its long chemical name, which sounds scientific and maybe a bit old-fashioned. Such a traditional name might inspire comfort; then again, it may make you think the drug is out-dated. Others might be tempted by number 3, since it has the “leuk-“ prefix of “leukemia”. Which drug is best?

Well, I cheated. They are all the same.

Anyone who has stood in front of a drugstore’s wall of pain-relief medication knows that drugs can have at least two different names. Aspirin and acetylsalicylic acid are the same. So are Advil and ibuprofen, and Tylenol and acetaminophen. If you’ve travelled to the United Kingdom, you may be aware that Tylenol is also known as paracetamol. Drugs can have three different names. In fact, drugs can have a long list of names, making it difficult for patients with chronic illnesses to remember if they have ever been prescribed a particular drug before.

There is, however, a method to this apparent madness, and a reason for assigning so many different names to the same molecule. Let’s look at Gleevec.

Gleevec is used to treat chronic myelogenous leukemia (CML). This form of cancer results in the abnormal proliferation of white blood cells. Their progenitors, which are produced by the bone marrow, fail to mature properly and the leukemic patient’s blood becomes filled with these immature white blood cells.

The main driver of this untamed proliferation is a protein called BCR-ABL. This macromolecule does not exist in healthy humans. It comes about because two pieces of DNA, which are normally not contiguous, become fused together. This creates a brand-new entity commonly referred to as the “Philadelphia chromosome” for the hometown of the two research institutes involved in its discovery. The healthy gene BCR is now fused to the equally healthy gene ABL, creating an aberrant protein, BCR-ABL, which drives cell proliferation uncontrollably.

In 1996, a study demonstrated that a synthetic chemical which targeted this aberrant protein could selectively kill cancerous cells in a Petri dish while leaving healthy cells unharmed. Its name was 4-[(4-methylpiperazin-1-yl)methyl]-N-(4-methyl-3-{[4-(pyridin-3-yl)pyrimidin-2-yl]amino}phenyl)benzamide.

This is the first identifier a drug gets: its chemical name. The chemical name, though difficult to pronounce and usually impossible to remember easily, is part of the lingua franca of chemists. Any chemist can look at this name and reproduce the molecular structure of the drug, because this chemical name is the product of very strict rules of nomenclature which indicate where each chemical group—acids, esters, amides, ketones—is.

For obvious reasons, the company that designed this compound shortened this linguistic atrocity and assigned their brand-new drug a code name. Code names lack any sort of personality: they are not unlike barcodes and help easily track the thousands of compounds at various steps of the development ladder within a company. The drug chemically known as 4-[(4-methylpiperazin-1-yl)methyl]-N-(4-methyl-3-{[4-(pyridin-3-yl)pyrimidin-2-yl]amino}phenyl)benzamide was assigned the code name ST1571.

The drug ST1571 soon entered a series of clinical trials designed to demonstrate first its safety, then its efficacy in actual human beings. Trials of this sort are usually divided into three main phases before a drug is allowed to be marketed. Most drug companies will begin the process of identifying their promising compound with a generic name and a brand name somewhere around the second or third phase of a clinical trial.

Since “ST1571” is an in-house designation, arrived at with no consultation with the outside world, the drug it represents needs a name that is unique in the world since it is about to be released on the market. That is when the drug company consults with two external bodies on designing a generic name. If the drug company is American, it begins negotiations with the United States Adopted Names Council (USAN) and with the International Nonproprietary Names Expert Group (INN).

“Before a statement of adoption is issued, the sponsoring firm, the USAN Council and the International Nonproprietary  Names Expert Group (INN) must agree on a single name for the substance.

“The USANC considers several criteria in evaluating potential names:
– Whether the names reflect the drug action and fit the naming scheme
– How well a name translates into languages other than English
– How easy a name is to pronounce and remember”1

By agreement between the drug company—Novartis—, the USAN Council, and the INN Expert Group, compound ST1571 became known generically as imatinib. The “ima-“ segment is known as the prefix and is absolutely meaningless. This is where drug companies can get creative. The “-tinib” part is known as the stem and indicates the class of drugs to which it belongs. Drugs ending in “-tinib” are cancer drugs targeting tyrosine kinases, a type of protein to which BCR-ABL belongs. Together, “imatinib” had to be a novel name never before used.

“Imatinib” is a simple enough name, but some generic names contain a third element, the infix. Take for example drugs that target the male sex organ to furnish it in the necessary blood supply for certain recreational and procreative activities. Sildenafil, vardenafil, and tadalafil all end in “-afil”, which indicates in the pharmaceutical world that they are phosphodiesterase 5 inhibitors.  The first two have yet another series of letters in common, the “-den-“ infix, that signifies that sildenafil and vardenafil have similar chemical structures. We are left with the meaningless but discriminating prefixes “sil-“, “var-“, and “tadal-“.1

If you are curious about what other suffixes mean, you can consult a table here.

While the generic name of a drug is what is typically used in communications between doctors and scientists all over the world, a drug company wants a unique name to distinguish their manufactured drug from the same drug released by another company down the road (e.g. a generic drug once the first company’s patent runs out). That’s where the brand name, also known as a trade name, comes in.

“Trade names often suggest a characteristic of the drug. For example, Lopressor lowers blood pressure, Vivactil is an antidepressant that might make a person more vivacious, Glucotrol controls high blood sugar (glucose) levels, and Skelaxin relaxes skeletal muscles.”2

Imatinib was originally given the brand name of “Glivec” by Novartis. The FDA objected to the spelling of the name, as they believed it would be too easy to confuse it with a drug that was used to treat diabetes. Novartis changed the spelling to “Gleevec” for the American market, and Gleevec was approved by the FDA in 2001 for the treatment of CML. In Europe, Australia, and Latin America, it retains its spelling of “Glivec”.

When Gleevec’s patent expires, another drug company can start to market its own version of imatinib under a different trade name. At this point, 4-[(4-methylpiperazin-1-yl)methyl]-N-(4-methyl-3-{[4-(pyridin-3-yl)pyrimidin-2-yl]amino}phenyl)benzamide will acquire its fifth name.

It is worth mentioning that not every drug follows this thorough nomenclature. Older compounds got their generic names from condensed versions of their chemical names. For example, ibuprofen, commonly used to relieve head aches and fevers, gets its name from a contraction of iso-butyl-propanoic-phenolic acid.

While drug aliases may seem confusing and unnecessary, they each play a specific role in the identification of a compound as it moves past the many milestones of drug development.

***

The drug imatinib was used simply as a convenient example. I have never worked at Novartis and I am not endorsing the drug.

If your interest has been piqued and you want to know more about the history of our understanding of chronic myelogenous leukemia and the development of imatinib, I recommend this great article.

I also skimmed over the rules for creating an original generic name. There is more than meets the eye: for the complete list of rules, consult this website.

 

(Feature picture by Mk2010)

 

1. American Medical Association. “Generic naming”. Accessed September 17, 2013. http://www.ama-assn.org/ama/pub/physician-resources/medical-science/united-states-adopted-names-council/generic-drug-naming-explained.page.

2. Silverman HM. “Overview of Generic Drugs and Drug Naming”. Accessed September 17, 2013. http://www.merckmanuals.com/home/drugs/trade-name_and_generic_drugs/overview_of_generic_drugs_and_drug_naming.html.

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