P-gp and increased drug effectiveness

[Sturnam]

Recently I've been reading about P-gp (Permeability glycoprotein) which is an integral protein of the BBB which has a lot of influence over what passes the BBB, as well as the efflux of drugs. It has been researched mainly as a possible way to get chemotherapy drugs into the brain.

If inhibited, it will allow an increase in the permeability of the BBB, and more drugs will be able to pass through. My question is, does anyone know if taking a P-gp inhibitor would increase the effectiveness of any given drug? It seems like this would mainly affect the hydrophilic drugs, and I'm not sure how many recreational drugs are especially hydrophilic, especially after a potential first pass metabolism.

Secondly, would natural sources (such as garlic, catechins from green tea, ginseng) provide any appreciable inhibition? I ask this mostly because as P-gp inhibition increases, the toxic side effects also increase, so maybe a mild P-gp inhibtion (from natural sources) would increase a drug's effects, without increasing the toxic side effects?

 

[MurphyClox]

If inhibited, it will allow an increase in the permeability of the BBB, and more drugs will be able to pass through. My question is, does anyone know if taking a P-gp inhibitor would increase the effectiveness of any given drug?[1] It seems like this would mainly affect the hydrophilic drugs[2], and I'm not sure how many recreational drugs are especially hydrophilic, especially after a potential first pass metabolism.

Secondly, would natural sources (such as garlic, catechins from green tea, ginseng) provide any appreciable inhibition?[3] I ask this mostly because as P-gp inhibition increases, the toxic side effects also increase, so maybe a mild P-gp inhibtion (from natural sources) would increase a drug's effects, without increasing the toxic side effects?

[1] In theory: YES.
This was discussed once for quinine (OTC p-GP inhibitor) and loperamide (usually a non-centrally active opioid and p-GP substrate) but IIRC practically all in vivo reports mentioned that it didn't work (my own experience says the same). This idea in particular is quite stupid due to probable MPTP-like metabolism of loperamide in the brain, but that's of course a completely different story. Still, in theory it works as you suggested.

[2] How did you come to this assumption? I just ask, because it's wrong. Have a look at loperamide again, which is indeed quite lipophilic. Here is a list of well-known substrates of p-GP (not complete of course; sorry that I fucked up the alphabetic order):

Actinomycin D, Bunitrolol, Daunorubicin, Celiprolol, Doxorubicin, Talinolol, Doxetaxel, Fluphenazin, Irinotecan, Perphenazin, Mitomycin C, Phenoxazin, Mitoxantron, Phenytoin, Paclitaxel, Fexofenadin, Tamoxifen, Terfenadin, Tenoposid, Cimetidin, Topotecan, Ranitidin, Vinblastin, Amprenavir, Vincristin, Indinavir, Cefazolin, Nelfinavir, Cefoperazon, Ritonavir, Erythromycin, Saquinavir, Levofloxacin, Cyclosporin A, Sparfloxacin, Tacrolimus, Domperidon, Atorvastatin, Ondansetron, Lovastatin, Amiodaron, Morphium, Digitoxin, Loperamid, Digoxin, Aldosteron, Propafenon, Dexamethason, Quinidine, Hydrocortison, Diltiazem, Colchicin, Mibefradil, Debrisoquin, Nicardipin, Losartan, Verapamil, Sestamibi

[3] Most probably not enough inhibition to make them "useful" in the proposed fashion, i.e. to facilitate BBB-penetration of p-GP substrates.

In general I strongly discourage any attempts to effectively inhibit p-GP. The protein got a purpose and you better don't fuck around with one of your most important protecting mechanism for your precious brain.

PEACE! - Murphy

 

[Sturnam]

How did you come to this assumption? I just ask, because it's wrong. Have a look at loperamide again, which is indeed quite lipophilic.

Well, I think I might need to clarify. I don't mean substrates for P-gp would be hydrophilic, I was thinking that once P-gp was inhibited, hydrophilic molecules would have an easier time getting through the BBB. I just made this assumption because the book I read said that lipophilic molecules can generally get through the BBB ok, but the BBB is especially good at stopping any hydrophilic molecules, partly due to P-gp. Then I just reasoned that with P-gp inhibited, hydrophilic molecules might be able to make it through a little bit easier.

In general I strongly discourage any attempts to effectively inhibit p-GP. The protein got a purpose and you better don't fuck around with one of your most important protecting mechanism for your precious brain.

Oh, I totally agree. Especially with how they mentioned that the brain toxicity went up extremely rapidly once P-gp inhibitors were introduced. Now, this was only in the context of chemotherapy drugs, but I don't really wanna be the guinea pig to find out if this applies to other drugs as well.

But thank you for your reply. I was mostly interested if there was any information on P-gp inhibitors being used in a recreational context.

 

[MurphyClox]

^...yeah, the best known "recreational context" is probably the mentioned example quinine/loperamide.

 

[Hammilton]

sertraline is an inhibitor, and only when I was on it did I ever notice an effect from loperamide: and it was not a positive effect.

 

[PsychedelicPeptide]

How about drinking some tonic water and taking your drug of interest?

It's effects on alcohol are clearly minimal. =P

 

[MurphyClox]

How about drinking some tonic water and taking your drug of interest?

It's effects on alcohol are clearly minimal. =P

Definitively not enough quinine contained! That was suggested before and IIRC, the needed amount tonic water were several liters to reach the desired effects. Plz consider the higher dilution of any compound in your blood after drinking several liters fluid, too... - Murphy