This post references both quercetin and quinidine
Steve Dyer wrote (several months ago):
> It turns out, however, that this behavior of loperamide is
> the result of the activity of a specialized ATP-activated "G protein"
> whose job it is to pump out such nasty stuff back across the blood
brain
> barrier as fast as it arrives. If you overwhelm the G protein by
keeping
> it busy with something else, loperamide once again becomes a
traditional
> mu opioid drug. Mice that lack this G protein which have been
administred
> loperamide behave like they've been given overdoses of morphine and
then
> they die. The only allusion I've seen to human beings has been a
recent
> abstract which reported that people taking 16mg of loperamide (8 2mg
caps)
> along with 600mg quinidine (a stereoisomer of quinine used as an
> antiarrythmic drug) exhibited uncharacteristic "respiratory
depression"; no
> comments on the degree of respiratory depression (a characteristic of
> mu-opiate activity), nor how it make them feel.
> I'm no expert on this subject, but there are probably whole families
of
> specialized G proteins which act as "pumps" against certain toxins
> (such mechanisms have been implicated in the development of resistance
> to certain toxic cancer chemotherapeutic agents such as cisplatin.)
> At the very least, this would suggest some caution using loperamide in
> people taking quinidine. 600mg of quinidine is hardly a harmless drug
> itself to produce an unquantified and itself potentially dangerous
high
> from an otherwise licit OTC product. But it makes you wonder what
else
> would be a suitable substrate for this G protein.
If there's any substrate suitable for turning loperamide
(e.g. Imodium brand) into a drug of abuse, I think
I know what it is.
There are several membrane proteins (MDR1, MRP1-6)
which have been identified (or tenatively identified) as
drug efflux pumps responsible for multidrug resistance
in cancer chemotherapy. They have in common the
ATPase binding cassette (ABC) [1].
Quercetin, a flavonoid, is known to inhibit these pumps
by inhibiting the ATPase activity [2, 3]. Quercetin is
easily absorbed in large quantity from the gut [4] and
well-tolerated by the IV route [5]. Quercetin is widely
available in oral dosage forms from so-called "health
food" stores, and in pure form over the Internet.
Therefore, I predict loperamide with quercetin is the
magic combination which would have opioid activity
in the central nervous system.
1. Kool et al, "MRP3, an organic anion transporter
able to transport anti-cancer drugs", PROC NAT
ACAD SCI, v 96, p 6914-6919.
2. Conseil et al, "Flavonoids: A class of modulators
with bifunctional interactions at vicinal ATP- and
steroid-binding sites on mouse P-glycoprotein",
PROC NAT ACAD SCI, v 95, p 9831-9836.
3. Shapiro and Ling, "Effect of Quercetin on
Hoechst 33342 Transport by Purified and
Reconstituted P-Glycoprotein, BIOCHEM
PHARMACOL, v 53, p 587-596.
4. Wiseman, "The bioavailability of non-nutrient
plant factors: dietary flavonoids and phyto-
oestrogens", PROC NUTR SOC, v 58,
p 139-146.
5. Ferry et al, "Phase I Clinical Trial of the
Flavonoid Quercetin: Pharmacokinetics and
Evidence for _in_Vivo_ Tyrosine Kinase
Inhibition", CLIN CANCER RES, v 2,
p 659-668.
http://groups.google.com/group/sci....=loperamide+quinidine&rnum=1#546746858d2fc5bd