Pharmacokinetics of "aqueous solvation" not related to hydrophobicity/lipophilicity?

[Nagelfar]

Pharmacokinetics of "aqueous solvation" not related to hydrophobicity/lipophilicity?

input pg. 25, its interesting to note a difference in "aqueous solvation" mentioned in a way that seems unrelated to lipophilicity (logP etc.) or am I misunderstanding? I always wondered why, for instance, cocaine HCl "dissolves" in a flash in water, but is considered a highly lipophilic substance. Does anybody know of any resources that mention how well lipophilic substances are "solvated" or not based upon other pharmacokinetic/dynamic factors than straight over-all hydrophilicity, etc?

 

[sekio]

[cocaine] is considered a highly lipophilic substance.

The free base is (technically), but I don't think I'd call cocaine HCl lipophilic. Normally lipophilicity and water solubility are two opposite ends of the see-saw. You make a compound more lipophilic, less will end up in water. And vice versa.

Even then, cocaine is actually really polar for a drug - it's one of the less lipophilic ones, actually. Compare something like PCP freebase with a logP>4.

Lots of amine drugs have this Janus effect where the salts are quite water soluble and the freebases are more fat soluble. A more useful determinant in these situations is the pKa, which will tell you what portion of the drug is protonated versus freebase at biological pH.

 

[belligerent drunk]

It's hard to call a charged molecule (ion) overall lipophilic unless it's really big. Cocaine freebase (the version where the nitrogen is not protonated) could be viewed as being fairly lipophilic, but as sekio said it's not that lipophilic as far as conventional drugs go. And at physiological pH the nitrogen is going to be protonated regardless of whether you smoke crack (freebase) or snort the HCl salt. Cannabinoids like THC are a good example of an overall lipophilic drug, because it has no basic or acidic centers, which means that at physiological pH it will still be uncharged and thus fairly lipophilic.

Lipophilic compounds are not solvated per se, but the water around the molecule is more structured than normally, but because there is no significant bond formation between the two, I wouldn't call it solvation in the conventional sense. That of course changes as soon as you introduce polar groups into the molecule, such as hydroxy- or oxo-, which can form hydrogen bonds with water and participate in dipole-dipole interactions. In that case, that part of the molecule will be "solvated". Salts, on the other hand, can be solvated pretty heavily. For one, the N(+)-H can donate a nice hydrogen bond and ion-dipole interaction is quite strong.

Sorry I don't really understand your question, so I hope I didn't just completely miss the point.

 

[Nagelfar]

Sorry I don't really understand your question, so I hope I didn't just completely miss the point.

Did you read the bottom portion of the page I linked? Conformational flexibility, steric influences, being a factor in how much "solvation" a compound has.

 

[sekio]

I think polar surface area is usually a good place to start to determine solubility.

You can run into compounds like methyl trioctyl ammonium chloride which are charged compounds and yet they are effectively insoluble in water due to the dominance of nonpolar interactions over the polarity of the charged N.