Drug Interactions July 7, 2008 4:30 pm
Posted by tungtide in Answers.Tags: drug development, drug interactions, drug metabolism, St. John's Wort, birth control, pharmacology, toxicology, opioids, CYP3A4, P450
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We have been a little light on posts over here so I thought I would bounce a post up that has to do with one of my interests. I’ve spent time working in the biotech/pharmaceutical industry and despite the negative reputation and bad press often associated with those companies (think about what comes to mind when you hear Pfizer or Vioxx) there are many skilled and diligent researchers that try to bring safe and effective drugs to market.
One of the many hurdles in developing a drug is understanding how a drug is metabolized. This is the process by which the body changes the structure of the drug to make it easier to excrete. A drug may be excreted unchanged or may be significantly altered in the process of traveling through the body. None of these things are known ahead of time, but all are determined in the “pre-clinical” phase of drug development. In this phase researchers work on the metabolism problems as well as looking at toxicity, bioavailability (how much of an oral dose will reach the bloodstream unchanged and active), and formulation (the coating and release mechanisms from pill form).
Why is metabolism important? The structure developed may be effective in treating your disease of choice, but it might very well be a metabolite of that structure that is the truly effective compound. Metabolites (and the parent compound) can have inhibitory or stimulatory effects on other enzymes in the body or on ion channels. The Human Ether A-gogo protein (hERG) is an ion channel in the heart that can be disrupted by some drugs and has been linked to deaths. It is vitally important for any new drug to avoid affecting this channel in the course of its action.
One of my favorite examples comes from combinations of drugs. St. John’s Wort is an herbal compound that most people believe has no side effects. This is simply a myth. Any compound you put into your body is a drug and will have an effect. The effect (and side effects) are dependent upon the dose but herbal compound are no more safe than any other drug but because they are regulated differently by the FDA there is little control over their administration.
Now, suppose you are a woman taking birth control pills (which are usually combinations of hormones), you are sexually active, and you do not want to have children. The normal dosing of The Pill changes the hormone balance in women to prevent ovulation but requires daily dosing to remain effective. The dosed hormones are metabolized to inactive metabolites by an enzyme in the liver: cytochrome P450 3A4 (abbreviated CYP3A4, part of the cytochrome P450 monooxygenase family of enzymes). So, daily dosing infuses the body with hormones and CYP3A4 works to remove those hormones.
Enter St. John’s Wort. This compound induces CYP3A4 by activating cellular receptors and telling the cell to make more enzyme. A woman taking both St. John’s Wort (SJW) and birth control pills is now in trouble. The SJW will increase levels of CYP3A4 in the liver and as a result more rapidly metabolize the birth control hormones. Despite daily dosing, the woman will quickly overwhelm the effects of the birth control pills and (because she is sexually active) become pregnant unless other forms of birth control are used.
The moral of the story is that anything you put into your body will have an effect (pharmacology) on biological systems. When those interactions are deleterious on their own (toxicology) you will see toxic side effects from the compound. Side effects can come from drug interactions (SJW and birth control) or from a compound acting at multiple biological receptors (opioids work on receptors to control pain but also prevent normal muscle function in the intestines and cause severe constipation).
Developing drugs is a difficult and costly process that involves the interaction of organs throughout the body with the drug and its metabolites. It is, however, an area that I find infinitely intersting and will be happy to answer any questions on the subject.
Thankyou Tungtide (LOVE the name) I shall precis this excellent information for my website with your permission and include link to this post of course. I think many women and teens take over the counter meds and still smoke , then without thinking, continue to use their hormonal contraceptive pills.
I have often used the word ‘metabolism’ in my website and article warnings about the risks of combining even vitamins and herbal products such as St. John’s Wort with hormonal contraceptives, yet I worry that this information is easily ’scrolled past’ or dismissed in the urgency to prevent pregnancy.
Your explanation, however, will ‘back up’ these warnings and hopefully encourage women, particularly those who are just starting their ‘contraception career’ to learn all they can about the ‘drugs’ they are putting into their bodies.
Understanding a bit more about individual metabolism and how their body reacts when they artificially alter their hormone levels will also help them to understand and successfully manage the ‘trial and error’ period when selecting a hormonal type of birth control.
Thank you
Carole,
You’re welcome to make use of the post as long as you link back here with the appropriate credit.
Drug metabolism is a much deeper field than I’ve outlined above and smoking is certainly a complicating factor. If you want to learn more look up information about the cytochrome P450 monooxygenases and xenobiotic metabolism as a place to start. A textbook like Goodman and Gilman’s “The Pharmacological Basis of Therapeutics” is another excellent and extensive source of information.
[...] posted yesterday on Scientician about drug interactions and herbal remidies. Anything you put into your body is a drug and will [...]
I agree with Dave…drug metabolism is a critical and very interesting component of medicine, in all species. All foreign substances (drugs) have effects. No drug has a “side effect”, rather they have known good/intended effects and adverse effects, as any prescribing doctor should be aware of. It is the clinician’s responsibility to weigh the pros and cons of any medication and decide what is best for the patient. They should also warn against any potential interactions, which may be often overlooked.
Herbal and “natural” supplements can get you into trouble as well because of interaction with other drugs and/or the components they themselves contain. There was a report a few years ago of an owner giving his dog chinese medicine balls instead of more traditional western medicine because he thought it was a more natural therapy (I cannot remember the ailment at the moment). The dog subsequently died. A necropsy and analysis of the medicine balls revealed toxic levels of mercury and lead, not to mention numerous herbs that were mixed in. The natural chinese balls were entirely natural, but deadly. Natural does not always equal good and safe.
How do you choose which medicines/herbs/foods to test a new drug with for possible interactions? How many different things do you test it with before releasing it into the market? Are there guidelines?
Bret makes an important clarification of my post: there are no “side-effects” in drug interactions, just positive and negative ones. Technically side effects are those caused by a single drug that happen in addition to the desired outcome.
Janelle, there are guidelines from the FDA about how to test for possible drug interactions. Rather than test against individual drugs, we use the mechanism behind the potential interaction to make the comparison. I’ll give an example:
CYP3A4 (mentioned in the post above) and another enzyme CYP2D6 are two of the P450 enzymes in the liver. Together they are responsible for the metabolism of about 75% of all drugs. This means that any drug that affects the function of these enzymes (as SJW did with 3A4) will have a high chance of changing the effects of another drug.
When a drug is prepared for clinical trials the metabolic profile is determined and the extent to which every (or at least the high abundance) enzyme contributes to the metabolism is known.
Then, when prescriptions are written and delivered the metabolic profiles of the drugs are compared by computer (and some common ones should be known by doctors and pharmacists) to look for potential drug interactions.