Fluorine, Fluorine, Fluorine Fluoriiine, We’re Begging Of You Please Dissolve Our Drugs

Thomas Midgley III, ^A Jebane Bzdury ^B and Günther Schlonk^C

Abstract: Your bond enthalpy’s beyond compare, you make the best non-stick cookware and we cannot compete with you fluorine.

Introduction

Solubility is one of the most important factors to address in the design of new drugs. Specifically, a drug molecule must be reasonably water-soluble in order to traverse the bloodstream (an aqueous medium under ideal circumstances) but still fatty enough to cross the lipid membranes of cells. This can be very challenging, as most drugs are small organic molecules, which are typically far more soluble in organic solvents like benzene and carbon tet. Vast amounts of work have been done on strategies to improve the solubility of drug molecules, without impairing their potency.¹ However, nobody is thinking outside the box. Instead of trying to make the drugs more soluble, what if we just made the blood more like an organic solvent instead?

Actually, some work has already been conducted on blood polarity modification, both intentionally and by accident. The average American’s blood is now 2-3% high-fructose corn syrup by volume, according to a 2022 study.² This number can rise as high as 7% in areas of the deep south, and wherever your mother lives. The authors of this study attempted to examine the effect of these syrup levels on the bioavailability of antidepressants, but couldn’t find enough people to make a control group. More relevant to this research are the findings of Coltrane and Connolly, who found individuals in Glasgow with chip oil levels as high as 0.2 M in their blood.³ They linked these findings to the ongoing Scottish heroin epidemic, by citing the synergistic effects of opiates and oleates.

We can reasonably assume that the good people of Alabama and Glasgow did not set out to alter their blood chemistry with intent. The same cannot be said of Wjżéjdkvó Lipinski, the pioneer of drug co-solvation (Figure 1).⁴ In 1970, Wjżéjdkvó was workingonaclassofdrugstocombatliverfailurecalled yennefogeraltins.

While the compounds showed great promise in vitro, their terrible solubility made their formulation challenging to the point of lethality. When administered intravenously, the compounds tended to precipitate in the bloodstream, with disastrous results. Desperation was Wjżéjdkvó’s salvation, as he discovered that if the patient’s blood alcohol content was above 0.5%, the drugs became soluble. As this state could be achieved by necking about five literatki⁵ of vodka, it was quickly dubbed “Lipinski’s rule of 5”. The Powiedz Tak Narkotykom (Poland’s equivalent of the FDA) approved Wjżéjdkvó’s compounds shortly afterwards, and pharmacies began offering half-price bottles of Belvedere with every prescription.

Ethanol has some merit as a drug co-solvent: it is of medium polarity, miscible with water, cheap, widely available and delicious. Unfortunately, it does have some downsides. These are mostly related to its biological activity, as evidenced by Lipinski’s death at 30 from liver failure.⁶ An ideal blood polarity modifier should be biologically inert, unlike ethanol, corn syrup and chip oil.

Fluorocarbons are the obvious solution to this riddle (Figure 2).⁷ The strength of the fluorine carbon bond makes them almost immune to the action of enzymes, and fluorine is frequently incorporated into drug molecules to enhance their metabolic stability. Unfortunately, polyfluorinated alkanes like perfluorooctane (1) are not miscible with water, so it would be necessary to entirely substitute a patient’s blood with fluorocarbon. While compounds like 1 can carry levels of dissolved oxygen sufficient to support life,⁸ most blood proteins would denature in such a polar solvent, likely causing Acute Arterial And Aortic Atrophy Generating Heart Haemorrhage (AAAAGHH). Fortunately, a subclass of fluorocarbons has already been developed to combat water immiscibility: perfluorosulphonates and perfluorocarboxylic acids (PFAS). These compounds, typified by PFOS (2) and PFOA (3) form water soluble salts with most cations, and find applications in everything from paint to panties. They’re so fantastic that people have started calling them “forever chemicals,” because if you fluorinated every molecule in your body to the same degree, you’d become immortal. They’ve even been dubbed “the new asbestos” by some government bodies, but this is probably hyperbola because they don’t taste anywhere near as good.⁹

As potential drug co-solvators, PFAS have a number of desirable characteristics. They’re cheap and widely available, but most importantly, there’s no evidence of any adverse biological effects originating from PFOS and PFOA.¹⁰ In 2018, the Trump administration commenced a thorough investigation into PFAS, and later that afternoon the committee concluded that “everything is fine” and that “PFAS are tremendous chemicals, the best chemicals”. Furthermore, the human body cannot eliminate molecules like PFAS, which is great because it means you only need to administer them once, and you’re set for life. Given these alluring properties, we set out to investigate if poorly soluble drugs could be made more bioavailable by adding PFAS to a patient’s bloodstream.

Results and Discussion

We selected Hünigs other other base (HOOB) as our model drug. This phenethylamine derivative shows promise as an antimundanative but its poor solubility prevents being orally administered, and it has to be applied as a DMSO lip-balm, or injected straight into a lymph node. To test the effects of our therapy, we employed the mouse model of Morosity and Conversation Deficit Disorder (MCDD) developed by McConkey and Nix.10 We then treated these mice with paper soaked in glucose, HOOB and varying levels of PFOS (Figure 3). Once the mice had died, their blood PFAS concentration was obtained by fluoromancy.¹¹

Morosity and Conversation Deficit Disorder is serious condition, which causes effected mice to off themselves from sheer boredom when isolated. Untreated mice typically survive 5-10 minutes post onset. Conventional therapies include stimulants and intensive podcast therapy. We observed that mice treated with only HOOB fared no better than untreated mice, but low doses of PFOS drastically lengthened their lifespans, almost up to an hour in some cases. At higher concentrations, (> 1 mM), all the mice experienced Acute Crises of Mortality (ACR) before they had the opportunity to kill themselves.

We found these results surprising, as we had not anticipated that a 1 mM blood concentration of PFOS would be enough to significantly alter its polarity, allowing HOOB to dissolve. This prompted us to perform further investigations, such as reading the Wikipedia page for PFOS. It transpires that the 1–10 mM range is the point at which PFOS begins to form micelles, and we believe that it is these micelles are transporting HOOB through the blood (Figure 4).

We then realised that micelles are the perfect drug vector, because they require much lower concentrations of co-solvent, compared to the amount that would be needed to alter the bulk-polarity of blood. We considered rewriting the paper to make it look like this was our idea from the start, but the 5th vodka was starting to kick in and it all seemed too hard.

As for the 100 mM and 1 M experiments, we performed autopsies on the mice (which is quite fiddly when you’re smashed on Stolichnaya) and observed some anomalies in their circulatory systems. It appears that at high concentrations, PFOS coats the walls of blood vessels with a bilayer-type structure resembling a capillary electrophoreses experiment. As such, blood components had begun to separate by size and charge, and the mice essentially chromatographed themselves to death.

Conclusion

We have demonstrated that low concentrations of PFAS in the blood can serve to solubilise non-polar drugs, and vastly increase their bioavailability. While perusing the Wikipedia page for PFOS, we did notice that a few people have some health concerns about PFAS, but we didn’t observe the formation of any cancers in our mice, during the hour they lived after the experiments. We also wish to restate the words of FDA spokesman D’Ernest Spannercroft, who said “at this time, the FDA has no credible evidence that PFAS pose any threat to the health of legal American residents” and “there, I’ve said it, now please untie me and return my wife and kids”. At worst, PFOS might be a very mild contraceptive, but that’s it. Finally, given that PFAS bioaccumulate, by 2050 we’ll all have PFAS micelles in our blood anyway, and there’ll be no need to sell them as supplements. Future work in our laboratory will aim to tackle the permeability of the blood-brain barrier, by poking some holes in it.

Notes and References

1. “A review of vast amounts of work that have been done on strategies to improve the solubility of drug molecules, without impairing their potency” T. Boy, C. Hill, 1992, J. Mus. Chem., 6(8), 1:30.
2. “GI Joe, but the GI now stands for Glycaemic Index” H. Lardy, F. Boombah, T. Ham-Münch, R. Lee-Large, T. Porker, B. Tubby. 2022, Corn Illustrated, 6, 2–4.
3. “Oh noooo, theres people wi oil fer blood n nat” B. Connolly, R. Coltrane, 2023, Proceedings of the Royal Society of Paisley, 43, 893–897.
4. “Combating liver-failure with ethanol: finally some good news for Poland” A. Sapkowski, W. Lipinski, 1970, Polish Journal of Chemistry, 6, 350–750 mL.
5. Note: A “Literatki” is a ~100 mL glass traditionally used to serve Vodka in Poland.
6. “Man who cures liver failure with ethanol dies” 1973, Izvestia
7. Note: We said it was obvious, why are you looking for a citation?
8. https://en.wikipedia.org/wiki/Liquid_breathing
9. “The Unburnable Chip” T. D. Fuego, H, Blumenthal, 1993, J. Food. Sci., 4, 180.
10. “A Murine Model for Morosity and Conversation Deficit Disorder” L. McConkey, B. Nix, T. Tagoviloa 2024, Journal of Concussion Science, 4th, 69 YD.
11. “Fluoromancy for Dummies” W. D. Merlin, 2008, Slapton University Press.