Feeling Bitter

Or, at least my mouth was, and wow did I ever want to know why.

I’m putting in on my pharmacology hat today because I’m just too fascinated!

Like many of us, apparently, the holidays struck me down with a major case of COVID-19.* When I had my first case back in 2022, during the Omicron wave, Paxlovid was being pretty strictly controlled. I recall sobbing on the videocall with my doctor when she gently, but firmly, refused to prescribe because I did not meet the criteria. I was frightened and desperate and so, so sick. It was a mild case, by any measure, but it did not feel like it at the time, especially when I was isolated from the rest of my family and confined to two rooms.

But this time, I got Paxlovid within 2 hours of my positive test. And lemme tell you that stuff is miraculous. There are many, many things wrong with applying capitalism to medical care and drug development. But this drug (not to mention the vaccines!)? We did good you guys. I did not spend days alternately freezing and burning. I did not sleep 15 hours a day. I did not tire from walking from one room to another. After three days I felt close to fine!**

And when the weird metal-mouth side effect showed up, I wasn’t even annoyed. I was FASCINATED. Why? How does a drug like this cause such a completely left field side effect? There are two potential hypotheses I could come up with: Either the drug is basic, or it’s binding. It turns out one is correct.

This is not Paxlovid. TBH it looks like an Altoid? Lucky person. Photo by danilo.alvesd on Unsplash

Drop the base

First of all, to me the taste wasn’t PURE metal. The best I could come up with is the flavor of fresh white grapefruit—right after you’ve brushed your teeth. No matter how one describes it, it is most assuredly BITTER.

What does that mean? Well many people might think bitter = base. We know that acids in general taste sour (think lemons), and bases, on the other hand, taste bitter (broccoli and baking soda are both slightly basic, and slightly bitter).

Bases have extra hydroxyl ions (OH-) in their solutions, and those activate specific receptors on the tongue (specifically the TAS2R receptor). So if the pill itself were relatively basic, it could certainly leave that bitter aftertaste just from having been in your mouth for the short time before you swallowed.

But there are a couple of reasons this doesn’t quite work. First, the aftertaste doesn’t leave. If the drug itself were basic, spitting out OH- ions, those are quickly washed away by your saliva (which is, interestingly, also slightly basic!). Or by a drink of water. Or by, well ANYTHING.

But the taste doesn’t go away with brushing your teeth. It varies from person to person, and can last hours to even days after (one story I found suggested only 6% of people get this side effect which I find LAUGHABLY underestimated). In my case, it tracked with the metabolism of the pills themselves. I didn’t have much of a taste after swallowing, it would rise slowly about an hour after, intensify and then remain for several hours after that. By the end of the 5 days I was able to actually tell when it was time for the next dose, because the metal taste would be entirely gone.

Secondly, if this were a question of extra OH- ions you could in theory especially conquer the taste with a quick swig of something acidic. The acid and base would neutralize each other. A quick nasty taste of toothpaste and grapefruit and done.

That doesn’t work. I tried.

Bind me up

You will recall up there I mentioned receptors. Receptors are some of the many workhorses of the body. They are protein structures on the membranes of your cells. The best analogy I usually use for them is locks. Things that bind to those receptors are like keys. Some are agonists, turning the receptor “on” and causing cascades of things to happen in the cell where the receptor is attached. Others are antagonists, turning the receptor “off.”*** Meaning it will NOT signal the cell or do things, or even cut off something the cell is doing. It’s like having one key to unlock, and one to lock.

You’ve got a TON of these receptors on your tongue, localized into your tastebuds. We used to think the tastebuds were all one type, like you have one chunk with sweet, while tastebuds on the left handle bitter and those on the right handle salty or something. None of that is true. They are all mixed in together into tastebuds all over your tongue (and inside of your mouth, and esophagus! And nose! And LUNGS in some cases, and stomach and…yeah).

One of those is the TAS2R receptor, which is specific to bitter. It respond to hydroxides (OH-) on chemicals. That’s the key that unlocks. In the case of most bitter things, the OH- molecules just bounce in and then out. You get the bitter taste, they get washed away.

But different keys can go into this lock. And some of them STICK. So if, for example, one of the drugs in Paxlovid happened to be a bitter agonist, and happened to have a high affinity for the receptor and nice long receptor hang time (there’s loads of potential complexity here with binding affinity vs efficacy vs occupancy, but that’s for the other pharmacology nerds out there), then even washing out your mouth would do nothing. You’d taste bitter.

And GUESS WHAT. That’s what happens! There are actually two drugs in Paxlovid, ritonavir and nirmatrelvir (how do you even pronounce…I don’t…ugh). The major one against Covid is actually nirmatrelvir, which helps stop the virus from replicating. Ritonavir is there to PROLONG the actions of nirmatrelvir. It does this by inhibiting an enzyme that breaks down things in the liver, called cytochrome P450 3A4 (which breaks down a LOT of important drugs, by the way, including a bunch of the antidepressants, a lot of chemotherapies, calcium channel blocker, hormones, caffeine…it’s busy). Inhibiting this enzyme means nirmatrelvir isn’t broken down as fast and can stay in the body longer doing its thing.

Both of these drugs are bitter, btw. But a November 2023 paper found that nirmtrelvir (even spelling that is a headache) makes a beeline for the TAS2R1 receptor. It binds there, and it does it well. It is so good at it that it’s gonna find those receptors through the drug amounts in your saliva, even when blood levels of the drug are at only 15 micromoles concentration, millionths of a mole. That, by the way, overlaps with the blood concentration of Paxlovid in a lot of patients.

Poof. Metal mouth.

Is it weirdly off putting? Sure. But is it fascinating? Oh YES.

Citation: Caronia L, Xi R, Margolskee RF, Jiang P. Paxlovid mouth likely is mediated by activation of the TAS2R1 bitter receptor by nirmatrelvir. Biochem Biophys Res Commun. 2023 Nov 19;682:138-140. doi: 10.1016/j.bbrc.2023.10.001. Epub 2023 Oct 2. PMID: 37806252.

Where have you been?

I hope it’s reading about wild turkeys (and if so, stay tuned for next newsletter because I’ve got stuff for YOU) and how people react to them on Staten Island. Because no, we don’t necessarily need to hunt them. We need to teach people how to behave with them.

Maybe it’s reading about bird DIVORCE. Yes, we often talk about how some birds mate for life. But really? Bird marriage can end too. The causes? Stress and climate change. Just like us really.

Maybe it’s reading about the Welsh Tidy Mouse! It’s so cute, this guy catches this mouse putting away all his things every night. Really, the mouse is merely exhibiting normal mouse behavior. We just interpret it as tidy and cute.

And maybe it’s reading a new book out by my colleague Rebecca Boyle! She’s written a lovely book about the human history and connection with the MOON. Check it out!

Where have I been?

Or rather, where WILL I be? I will be in Houston on February 20, at the Museum of Natural Science, to talk about PESTS. Come on out and say hi!!

Anti-Discourse Actions

As mentioned here, I am trying very, very hard to stay out of Discourse. I don’t want to waste my brain power on finding out who to scold or who to sneer at or flailing in my angry and grief at people who have nothing to do with it. I am tired of having to start over and over again from scratch, using all my time and energy dodging and weaving as more and more bad actors as discovered. I am especially tired because many of those places are media outlets. Where I need to write to make money. So instead of Discount, I am saving my energy for taking action.

1. This week I talked to a contact of mine who works in dog fostering, and it turns out that they can always use dog sweaters, especially for their little smol bois. And I crochet. In fact, I’m really good at dog sweaters! I got some free yarn donated and three wee sweaters are off to make some very good pups look very adoptable. (Amusingly, I didn’t have much control over the color or type of the yarn, so some of these dogs are going to be rocking Quiet Luxury style in expensive Icelandic wools, cashmere and mohair. I hope they like it?)

2. Went to Substack’s office hours to ask them to please make clear that far-right views won’t be tolerated. I even did it twice!

3. I signed up for a new initiative that I hope to tell you more about soon!

*I feel weirdly like I somehow need to offer my excuses around this, because…well the internet is really awful. I’ve got all my vaccines and boosters. I still mask indoors. I still limit my goings out to eat, and try to eat outside. I’ve had more than one panic attack when someone in a bar coughed. I am careful. Careful on not, no one deserves to have Covid. In the words of Haymitch Abernathy: Remember who the real enemy is.

**Note: Rebound cases are definitely common. I got lucky this time.

***It can get WAY more complex than this. Not today.