Common Crazy Med Crap Index
Pharmacokinetics Overview | Pharmacology Index | Absorption & Distribution

“If they’re both anticonvulsants, why do I have to take twice as much Lamictal (lamotrigine) when I also take Tegretol (carbamazipine)? Shouldn’t it be like Depakote (divalproex sodium)? You only take half as much Lamictal as you would if you didn’t take anything else.” It also raises questions that haven’t been satisfactorily answered, such as, “Why is it that the more Neurontin (gabapentin) you take, the less you absorb?” PK can give you a glimpse into the future, as active metabolites1 can become patent extenders drugs themselves, such as Invega (paliperidone), which is based on Risperdal’s (risperidone) active metabolite.

1.  Process of Elimination

1.1  Estimated Time of Departure

Throughout this site we use what is known as plasma clearance, which is the half-life (preferably the median half-life after steady state is reached) times five. Based on Julien’s calculations from A Primer of Drug Action, although Julien takes it out to six. Half-life times five-to-six days is a fairly well accepted rule-of-thumb estimate2 for anyone who is an extensive (i.e. normal) metabolizer of the CYP450 and/or UGT substrates in question and has no kidney (renal) or liver (hepatic) problem.

A more accurate number requires a lot more data, including your weight, the dosage you’re taking, and various bioavailability data covered in the next section.

However, because it is an estimate, and there are all sorts of other factors involved, a medication can be gone a lot sooner or hang around a lot longer than expected. If the former it means you may need to take more, take the med more often, or both. If the latter it means you need to take less, take it less frequently, or both. Either can affect adverse reactions, although it’s far more likely you’ll have side effects issues if it takes longer for you to clear a drug.

1.2  Liver and Enzymes

The most common way crazy meds are eliminated, or active metabolites are created3, is via CYP450 metabolism in your liver. Practically every drug we deal with that is metabolized by a CYP450 enzyme is metabolized by (is a substrate of in PK talk) one or more of the following enzyme / gene systems: CYP1A1/2, CYP2D6, CYP2C9, CYP2C19, and CYP3A4/5.

  • A plurality of crazy meds are metabolized by CYP2D6, and approximately 7% of the population are poor metabolizers of those drugs. These people actually qualify as “med sensitive,” unlike those who just complain about side effects that are no worse than what most people deal with4.
    • Drugs metabolized by CYP2D6 are cleared faster if you drink alcohol.
  • Drugs metabolized by CYP3A4 comprise the second-largest share of crazy meds (the majority, or a large plurality of non-crazy meds are substrates of CYP3A4/5), and are especially sensitive to, and have numerous drug-food and drug-supplement interactions.
  • Drugs metabolized by CYP2C19 are often overlooked, yet ~20% of the Japanese population are poor metabolizers, and 18% of the Swedish and Ethiopian (!) populations are ultra-rapid metabolizers.5
  • Drugs metabolized by CYP1A2 and some UGTs (see below) are cleared a lot faster if you smoke or are exposed to a fair amount of second-hand smoke.
  • When a drug is metabolized by multiple enzymes, some enzymes aren’t involved very much, so they may not make much difference. Unless some researcher discovers that they do more work than everyone first thought.
  • Just as there are histamine, serotonin, and other neurotransmitter receptors throughout your body (more on that on a med’s Pharmacodynamics page), there are CYP450 genes in your brain, and that may have something to do with how the meds work.
    • For example - you have serotonin receptors throughout your digestive system, which is why SSRIs, especially Paxil, are good for things like IBS and Chron’s disease.
    • While most SSRIs aren’t all that selective, one thing that easily explains why they vary so much in how well they work for so many different applications is their effects on CYP450 genes in your brain.

Stick to your treatment plan with buttons and magnets. 2.25″ $4 & 3.5″ $4.50 at Straitjacket T-shirts
Pile of Pills buttons at Straitjacket T-shirts
Pile of Pills
Vaccines Cause Immunity buttons at Straitjacket T-shirts
Vaccines Cause Immunity
Medicated For Your Protection magnets at Straitjacket T-shirts
Medicated For Your Protection
Fuck Bipolar buttons at Straitjacket T-shirts
Fuck Bipolar

Another system involved in the clearance of meds are the UGTs’6. The antiepileptic drugs Lamictal (lamotrigine), the valproates (Depakote (divalproex sodium), Depakene (valproic acid), Stavzor (valproic acid delayed release) and whatever sodium valproate/valproate sodium is called where you live), Tegretol (carbamazepine) and Dilantin (phenytoin) are most associated with UGTs due to the complicated mechanics of switching to Lamictal from any of the others in that list. Estrogen-based birth control, and perhaps endogenous estrogen (i.e. the estrogen you produce yourself), induces (causes you to produce more) UGT1A1, which clears Lamictal faster. Which is why estrogen-based (i.e. practically everything women use) birth control and, occasionally, even a woman’s cycle can mess with Lamictal.

  • Like those metabolized by CYP2C19, there are more drugs metabolized by the UGTs than most people realize, just as there are more drugs metabolized by more than one enzyme and enzyme system than originally thought!
  • Smoking induces UGT1A1, UGT1A4, UGT1A6, UGT1A8, UGT1A9, and UGT1A10, as does Tegretol (carbamazepine). That covers a lot of crazy meds, from amitriptyline to Zyprexa, and non-crazy meds, from acetaminophen (AKA Tylenol) to Zocor.

So why should you care how a drug is cleared? Or which enzymes in your liver it messes with?

Got all that? Good. It will be on the test at the end of the week.
But wait, there’s more…

  • When a drug inhibits an enzyme, it slows down the metabolism / clearance of any substrates by interfering with how well the enzyme does its job.
  • When a drug induces an enzyme, it speeds up the metabolism / clearance of any substrates by causing your liver to produce more of those enzymes. Too much induction can be bad for you, which is one reason why blood panels are required for some drugs.
  • When a drug suppresses an enzyme, it slows downs the metabolism / clearance of any substrates by causing your liver to actually stop producing (AKA the genetic expression of) those enzymes. I don’t know if this can cause problems or not. Very few meds suppress CYP450 enzymes, and the only crazy med I’ve found that suppresses the expression of an enzyme is Provigil (modafinil).
  • If a drug inhibits and/or induces the enzyme(s) involved in its own metabolism, that has already been taken into account for its half-life, etc.
  • Induction and inhibition are classified as weak, moderate, or strong. “Weak” means it’s of interest only to researchers and other PK geeks. “Moderate” means it could have an impact, either when combined with other meds or when taken by someone with a genetic polymorphism involving the same CYP450 gene. “Strong” means you bet your ass it’s going to affect other meds.
  • And because things aren’t complicated enough, there are frequently new and often conflicting studies regarding the enzymes involved in a drugs clearance, the extent to which each one is involved, and the potency, if not very existence, of a med’s inhibition and/or induction properties. So this page is subject to change.

These will stick around longer than most side effects. More ways to be stuck-up at Straitjacket T-shirts. All stickers $5 each. Available in packs of 10 and 50.
Medicine Is The Best Medicine stickers at Straitjacket T-shirts
Medicine Is The Best Medicine
Vaccines Cause Immunity stickers at Straitjacket T-shirts
Vaccines Cause Immunity
Mental Illness is NOT Contagious stickers at Straitjacket T-shirts
Mental Illness is NOT Contagious
Medicated For Your Protection stickers at Straitjacket T-shirts
Medicated For Your Protection

One more thing - because you piss away 90–100% of the remnants of anything you take, and almost all crazy meds (and all medications in general, including OTC drugs) affect and/or are affected by your liver, if you have a problem with either or both of your liver and kidney(s), most, if not all of this information is going to be very different as far as you’re concerned. We can’t cover everything. You’ll need to talk to your pharmacist, your doctors, and, if possible, try to get your doctors to talk to each other about it.

What can you take away from the above information? A few things.

  • If you have a history of side effects that usually don’t last very long for most people, but never seem to go away with you, the side effects that usually are mild-to-moderate really are much, much worse for you,9 or even if it seems like you need to take a med twice a day when it’s supposed to be a once-a-day formula, you may not have the standard set of CYP450 enzymes (known as genetic polymorphism). If the drugs you have taken in the past, including non-crazy meds, are all substrates of the same enzymes, you and your doctor(s) can infer something is going on.10
  • Your doctor can order tests for some CYP450 polymorphism. CYP2D6 is polymorphism common and the test is relatively inexpensive - although it might not catch intermediate metabolizers. Tests for the other enzymes can be prohibitively expensive, if they exist at all.
  • The majority of drug-drug, drug-supplement, and drug-food interactions are based a med’s relationship with CYP450 and UGT enzymes.

GlobalRPh’s PK Tools

Keep Crazymeds on the air.
Donate some spare electronic currency
you have floating around The Cloud

Common Crazy Med Crap Index
Pharmacokinetics Overview | Pharmacology Index | Absorption & Distribution

2.  Bibliography

Stahl’s Essential Psychopharmacology: Neuroscientific Basis and Practical Applications (Essential Psychopharmacology Series) Third edition by Stephen M. Stahl © 2008 Published by Cambridge University Press.
Primer of Drug Action 12th edition by Robert M. Julien Ph.D., Claire D. Advokat, Joseph Comaty © 2011 Published by Worth Publishers.
Genetic Basis of Drug Metabolism
1 Sometimes the pill you take isn't the actual medication. Or it is, and your body converts into another drug as well. These are known as active metabolites. They complicate the hell out of determining when a med is finally clear of your system, as they have their own half-lives and can be eliminated via different CYP450 enzymes, or entirely different mechanisms, than whatever it was that you swallowed.

2 Like converting Celsius to Fahrenheit for the weather conditions in commie unamerican countries that use the metric system: double it and add thirty. It's close enough for weather, but you don't want to use it for baking or lab work.

3 When an otherwise inert medication is specifically designed to be converted to an active metabolite which actually does something, it is called a prodrug. The term prodrug can apply to any inert, or mildly active med that converts to a real drug, but it is usually reserved for meds designed that way. E.g. Risperdal usually isn't call a prodrug, but Vyvanse is. Most prodrugs must be swallowed. Sticking them under your tongue is a waste of a pill. A few can be injected, such as Risperdal Consta.

4 So please STFU with your rationalization about why you can't take any medication. Either you want to get better or you don't. If you don't want to get better, find another website, buy a bunch of Elron Weil-Breggin books, and pray to Xenu while you take a bunch of overpriced supplements. Even if you are a poor or intermediate metabolizer of one or more CYP450 or UGT alleles, so are 15-20% of the people on the planet. Most of us are dealing with it, so can you.

5 I can't think of two more disparate peoples. Did Vikings provide the transportation for the Jews who migrated to Axum? Did they return with a bunch of women and Swediopian babies?

6 UGT: Uridine 5'-diphospho-GlucuronosylTransferase. AKA UDP-GlucuronosylTransferase. AKA the liver's garbage collector.

7 Although you can have variable metabolism with any CYP450 or UGT enzyme, CYP2D6 is the most common, or at least the most studied and deemed the most “clinically relevant” by whoever decides that sort of thing.
Poor metabolism exists when people are either missing parts (alleles, primarily *3, *4, and *5, possibly others as well) or those alleles of the CYP gene are just hosed. This is called genetic polymorphism, and exists in anywhere from 5–12% of the Caucasian population (depending upon which of the now numerous studies you read), 5–7% of the African population, and 1–2% of the Asian population. I haven’t found numbers for other ethnic groups. Good luck figuring out the percentages in this multi-ethnic world.
There are also intermediate metabolizers, who aren’t missing anything, their *10 and *41 alleles are just lazy. I.e. they don’t produce the required enzymes as well as extensive (normal) metabolizers. As the intermediate metabolizers are a relatively recent discovery, the percentages are even more vague. I’ve seen 10–35% for Caucasians and 10–25% for Asians. 25% for both groups is my current best guess. I haven’t found numbers for anyone else. Intermediate metabolizers usually have few, if any problems, with the therapeutic dosage of a single medication metabolized by CYP2D6. It’s when you take more than one drug, or take a drug that is metabolized multiple times or is otherwise extensively by CYP2D6 that problems happen.
On the other end of the spectrum are the rapid metabolizers, people with multiple copies of the alleles involved in the CYP2D6 metabolism. They’ll burn through those meds very quickly. The population numbers are smaller, around 0.5–2% regardless of ethnicity, although one study I came across found over 20% of people of Eithiopian descent had multiple alleles! Go team Addis Ababa!
There is a test your doctor can order if you suspect variable CYP2D6 metabolism is a problem. With any luck they look for intermediate and rapid metabolizers as well. Tests for other CYP450 enzymes exist, but they are way more expensive.
Being a poor, intermediate, extensive, or rapid metabolize with one CYP450 gene doesn’t mean you’ll be the same way with another. When I still drank alcohol I could drink most people under the table and hangovers weren’t much of a problem for me, but it takes forever for me to process anything involving CYP2D6.

8Specifically by preventing the enzyme from fully binding to the drug. It’s more complicated than that, but you’ll have to do your premed homework yourself.

9 And you consistently get a severe form of the same side effect. Because most people who take crazy meds for the very first time and have no idea what side effects are like think they’re med sensitive. or you’re just a whiny brat who can’t understand the philosophy of which sucks less)

10 Here are some websites to look up which enzymes are used by what meds. None of these is complete, but they are all extensive:
Big table of CYP450 substrates, inhibitors & inducers.
Big table of UGT substrates, inhibitors & inducers.
Alphabetical list of drugs, with substrates, inhibition, and induction.

11 See footnote 2 above. The good news is generic manufacturers are required to be at least 90% sure of everything being within the 80–125% range.12 If we see any evidence of a generic manufacturer ever doing more to establish the 80–125% bioequivalence standard than giving one small dose of the med to the 20 white guys who have already sold their monthly allotment of plasma, we’ll note it.

13 Also check {{$$brandname}}’s Useful Links page for any other PI sheets that may be available. Sometimes additional PK data (along with other side effects, etc.) can be found on PI/SPC sheets from other countries.

14There are a few other occasions where these data are helpful. E.g. if you don’t have enough of a history to infer you have CYP and/or UGT genetic polymorphism and you need numbers to compare with blood tests of some sort. Or you got a stock tip and have the bioavailability numbers from a drug under development and wish to compare it with an existing med it will be competing with. Whatever. Just don’t ask us to do the math for you. Because there’s a lot of math involved.

Pharmacokinetics 101 - Metabolism & Elimination by Jerod Poore is copyright © 2010 Jerod Poore

Last modified on Friday, 15 April, 2016 at 20:19:49 by JerodPoorePage Author: Jerod PooreDate created: 14 December 2010

All drug names are the trademarks of someone else. Look on the appropriate PI sheets or ask Google who the owners are. The way pharmaceutical companies buy each other and swap products like Monopoly™ real estate, the ownership of any trademarks may have changed without my noticing.

Page design and explanatory material by Jerod Poore, copyright © 2003 - 2016. All rights reserved.
Keep up with Crazymeds and and/or my slow descent into irreparable madness boring life. Pick your preferred social media target(s):

Almost all of the material on this site is by Jerod Poore and is copyright © 2003, 2004, 2005, 2006, 2007, 2008, 2009, 2010, 2011, 2012, 2013, 2014, 2015, and 2016 Jerod Poore. Except, of course, the PI sheets - those are the property of the drug companies who developed the drugs the sheets are about - and any documents that are written by other people which may be posted to this site will remain the property of the original authors. You cannot reproduce this page or any other material on this site outside of the boundaries of fair use copying without the express permission of the copyright holder. That’s usually me, so just ask first. That means if want to print out a few pages to take to your doctor, therapist, counselor, support group, non-understanding family members or something like that - then that’s OK to just do. Go for it! Please. As long as you include this copyright notice and something along the lines of following disclaimer, I’m usually cool with it.

All rights reserved. No warranty is expressed or implied in this information. Consult one or more doctors and/or pharmacists before taking, or changing how you take any neurological and/or psychiatric medication. Your mileage may vary. What happened to us won’t necessarily happen to you. If you still have questions about a medication or condition that were not answered on any of the pages you read, please ask them on Crazy Talk: the Crazymeds Forum.
The information on Crazymeds pertains to and is intended for adults. While some information about children and adolescents is occasionally presented (e.g. US FDA approvals), pediatric-specific data such as dosages, side effects, off-label applications, etc. are rarely included in the articles on drugs or discussed on the forum. If you are looking for information regarding meds for children you’ll have to go somewhere else. Plus we are big pottymouths and talk about S-E-X a lot.
Know your sources!
Nobody on this site is a doctor, a therapist, or a pharmacist. We don’t portray them either here or on TV. Only doctors can diagnose and treat an illness. While it’s not as bad as it used to be, some doctors still get pissed off by patients who know too much about medications, so tread lightly when and where appropriate. Diagnosing yourself from a website is like defending yourself in court, you suddenly have a fool for a doctor. Don’t be a cyberchondriac, thinking you have every disease you see a website about, or that you’ll get every side effect from every medication1. Self-prescribing is as dangerous as buying meds from fraudulent online pharmacies that promise you medications without prescriptions.
All information on this site has been obtained from the medications’ product information / summary of product characteristic (PI/SPC) sheets and/or medication guides - which is all you get from sites like WebMD, RxList, NAMBLA NAMI, etc., the sources that are referenced throughout the site, our personal experience and the experiences family, friends, and what people have reported on various reputable sites all over teh intergoogles. As such the information presented here is not intended as a substitute for real medical advice from your real doctor, just a compliment to it. You should never, ever, replace what a real doctor tells you with something from a website on the Internet. The farthest you should ever take it is getting a second opinion from another real doctor. Educate yourself - always read the PI/SPC sheet or medication guide/patient information leaflet (PIL) that comes with your medications and never ever throw them away. OK, you can throw away duplicate copies, but keep at least one, as that’s your proof of purchase of having taken a med in case a doctor doubts your medical history. Plus they take up less space than a bottle, although keeping one inside of a pill bottle is even better.
Crazymeds is not responsible for the content of sites we provide links to. We like them, or they’re paid advertisements, or they’re something else we think you should read to help you make an informed decision about a particular med. Sometimes they’re more than one of those things. But what’s on those sites is their business, not ours.
Very little information about visitors to this site is collected or saved. From time to time I look at search terms used and which pages they bring up in an effort to make the information I present more relevant. And the country of origin, just because I’m geeky like that. That’s about it. Depending on how you feel about Schrodinger, our privacy policy should either assuage or exacerbate your paranoia.
Crazymeds is optimized for ridiculously large screens and browsers that don’t block ads. I use Firefox and Chrome, running under Windows 72. On a computer that sits on top of my desk. With a 23 inch monitor. Hey, at least you can make the text larger or smaller by clicking on the + or - buttons in the upper right hand corner. If you have Java enabled. Like 99% of the websites on the planet, Crazymeds is hosted on domain running an open source operating system with a variety of open source applications, including the software used to display what you’ve been reading. As such Crazymeds is not responsible for whatever weird shit your browser does or does not do when you read this site3.
Crazymeds now uses a secure server, but it is not so secure that you can discuss anything having to do with nuclear power facilities, air traffic control systems, aircraft navigation systems, weapons control systems, or any other system requiring failsafe operation whose failure could lead to injury, death or environmental damage. Just so you know. So if you’re mentally interesting and have a job that deals with that sort of thing, talk about said job elsewhere. Otherwise feel free to discuss your meds and brain cooties.
No neurologists, psychiatrists, therapists or pharmacists were harmed in the production of this website. Use only as directed. Void where prohibited. Contains nuts. Certain restrictions may apply. All data are subject to availability. Not available on all mobile devices, in the 12 Galaxies Guiltied to a Zegnatronic Rocket Society, or in all dimensions of reality. Hail Xenu!

‘Everything is true, nothing is permitted.’ - Jerod Poore

1 While there are plenty of books to help you with hypochondria, for some reason there’s not much in the way of websites. Then again, staying off of the Internet is a large part of curing/managing the disorder.

2 Remember kids, Microsloth operating systems are like TOS Star Trek movies with in that every other one sucks way, way more. With TOS Star Trek movies you don’t want to bother watching the odd-numbered ones. With Microsloth OS you don’t want to buy and install the even-numbered ones. Anyone who remembers ME and Vista knows what I mean.

3 Have I mentioned how open source operating systems for commercial applications is one of the dumbest ideas in the history of dumb ideas?* I don’t even need my big-ass rant any more. Heartbleed has made my case for me. And that’s just the one that got all the media attention. The very nature of an open source operating system makes security as much of an illusion as anonymity on teh Intergoogles. Before you flip out too much: the domain Crazymeds is hosted on uses a version of SSL that is not affected by the Heartbleed bug. That’s one of the many reasons why I pay a lot of money and keep this site on Lunarpages.

* Yes, I know I’m using open source browsers. I also test the site using the now-defunct IE and Safari browsers. Their popularity - and superiority - killed IE and Safari, so that’s why I rely on the open source browsers. It’s like brand vs. generic meds. Sometimes the generic is better than the brand.

Enable Crazymeds’ Financial Solvency!

Enable Crazymeds to keep spreading our knowledge. Donate some spare e-currency you have floating around The Cloud.

Improve Your Social Media Skills


Follow our Highly Irregular Updates and Paranoid Rants Other News


Square this Circle

For Site News and NeuroPsych Research


Show us teh like™

Crazymeds: The Blog

For Site News and Crap that Distracts me from my Fucked-up Life

Crazymeds’ Tumblr

Mentally Interesting Advocacy

OpEd News

Daily Kos

Sites That Probably Suck Less Than Crazymeds

Crazymeds Merchandise

Available at Straitjacket T-Shirts

Vaccines Cause Immunity bumpersticker at Straitjacket T-Shirts

Stuck Up
All stickers $5. Now Available in Packs of 10 & 50

Mentally Interesting button at Straitjacket T-Shirts

Button It!
2.25″ $4 & 3.5″ $4.50. Now Available in Packs of 10 & 100