Bioavailability of oral cocaine?

[MurphyClox]

I already asked this on a different board (like Bluelight much with a much darker tone ) but somehow I'm not satisfied with the given answers. My question:

Confusion about oral bioavailability of cocaine:
Just checked Wiki about the bioavailability of orally applied cocaine. The value given is similar (i.e. in the same range) to the intranasal route.
But: Cocaine contains 2 esters and the pH of our stomach will cleave at least the benzoylic one IMO. Also I remember to have read that cocaine undergoes an effective first-pass-effect. That would exclude the oral route as useful, because from the remaining amount that successfully passes through the stomach, nearly everything would get metabolized before it reaches the brain.
...Therefore my confusion! I always thought that plain swallowing cocaine is of no use.

???

Thx, Murph


Let me share with you some of the already given answers (to shorten the discussion here a bit)

I think it is absorbed faster than it is cleaved, so is still available. coca tea or coca wine are active, so I supose in the absence of an esterase the hydrolysis in acid is pretty slow, most chemical methods to effect this hydrolysis need strong acid and heat and an hour or so. basic hydrolysis would probably be faster..

Agreed. The pH-catalyzed hydrolysis is probably not very effective. Probably...

As for bioavailability:
Nasal mucosal versus gastrointestinal absorption of nasally administered cocaine.
Fattinger K, Benowitz NL, Jones RT, Verotta D.
Eur J Clin Pharmacol. 2000 Jul;56(4):305-10.

Abstract:
OBJECTIVE: Several xenobiotics, including cocaine, are dosed by the nasal route for systemic effects. The aim of this study was to estimate and compare cocaine input into the systemic circulation after oral and nasal dosing, and to determine the relevance of local absorption through the nasal mucosa. METHODS: Cocaine was administered to healthy volunteers through the intravenous, oral, and nasal routes. Cocaine serum concentrations were measured at frequent intervals. From these data, the gastrointestinal, nasal, and nasal mucosa input rate functions were determined using nonparametric, subject-specific population deconvolution. RESULTS: After oral dosing, cocaine input into systemic circulation increased slowly and peaked around 45 min after ingestion. The median systemic bioavailability after oral dosing was 33 %. After nasal dosing, drug input was substantial even during the first minute and showed two peaks at 10 min and 45 min after ingestion. Since the second peak after nasal dosing closely resembled drug input after oral administration, we hypothesized that, after nasal administration, a part of the dose is swallowed and thereafter absorbed gastrointestinally. The data from the sessions with nasal cocaine administration were reanalyzed assuming the same shape for gastrointestinal drug input as after oral dosing. The fraction absorbed through the nasal mucosa was estimated to be 19 % (95 % CI: 11-26% ). The fraction absorbed through the nasal mucosa contributed 31 % (95 % CI: 23-37% ) of total systemic cocaine exposure. CONCLUSIONS: Our data suggest that the main reason addicts prefer nasal to oral cocaine dosing is faster absorption, enhancing the subjective effects rather than higher bioavailability.
Link

So it looks like that 2/3 of the nasal cocaine is absorbed through the GIT.

OK, Longimanus seems to have answered my question. But for some reason (gut-feeling, sorry) I still have my doubts.

In another thread here @Bluelight, Swilow stated that

Cocaine is largely destroyed in the stomach also.

taken from here: http://www.bluelight.ru/vb/showthread.php?t=394449

YO Swilow! If you read those lines, plz tell how you came to this statement?

I was somehow convinced that oral coke is a huge waste of the expensive compound. Now I'm rather confused. Comments from the sapient section are welcome. Please help me out here.

Thank you very much!

Peace! Murphy

 

[LuxEtVeritas]

i have seen multiple studies showing bioavailability of PO same as IN with simply slower onset and somewhat longer duration

was surprised, but that was what i found

 

[LuxEtVeritas]

some seemed to indicate about 30% as an average but the only study i read directly comparing to IV seemed to indicate 10% and that may go for both PO and IN...

 

[Hammilton]

i was pretty sure it was at least somewhat bioavailable

(sorry, this is the new me, for some reason my computer lost my auto-login and because I can't get into my hushmail account without paying, I'm just gonna use this new one- please forward any PMs here!!)

 

[fastandbulbous]

There isn't a 1st pass metabolism of cocaine as the enzyme responsible (plasma pseudoesterase) as the name implies, isn't exclusively situated in the liver.

The methyl ester isn't hydrolysed that quickly, even in 0.1M HCl at 37'C - most gets absorbed before that happens. The short half life (via any route - obviously a clue!) is due to the aforementioned plasma pseudoesterases

 

[LuxEtVeritas]

there is definitely absorption issues of some nature than affecting all other routes than IV which of course is commonplace, but again IN and PO are about equal as both routes have their 'issues', first pass as noted above not being one of them for oral

one of the studies i found of interest and alluded to above in the 10% oral bioA notation, though most other notations seemed to indicate ~30% this seemed more authoritative...thoughts...?:

Cocaine pharmacodynamics after intravenous and oral administration in rats : Relation to pharmacokinetics
Auteur(s) / Author(s)
FANG MA (1) ; FALK J. L. (1) ; LAU C. E. (1) ;
Affiliation(s) du ou des auteurs / Author(s) Affiliation(s)
(1) Department of Psychology, Rutgers, The State University of New Jersey, 152 Frelinghuysen Road, Piscataway, NJ 08854-0820, ETATS-UNIS
Résumé / Abstract
Rationale: To design optimal dose regimes for oral cocaine, it is essential to characterize pharmacokinetics (PK) of cocaine after IV and PO administration. Objectives: To investigate the absolute bioavailability of oral cocaine, its effectiveness and the relation between PK and PD in a within-subject design. Methods: We used the effects of IV and PO cocaine on a contingency-controlled timing behavior, the differential reinforcement of low rate schedule (DRL 45-s) in 3-h sessions, as the PD measures [i.e., the shorter-response rate (srr) and the reinforcement rate (rr)]. Cocaine PK parameters were determined by simultaneous modeling of the concentration-time profiles (CTPs) after IV 2 mg/kg and PO 20 mg/kg cocaine administration. The absolute oral cocaine bioavailability was determined pharmacokinetically (F) and pharmacodynamically (Fsrr and Frr). Results. IV and PO cocaine increased the shorter response rate and decreased the reinforcement rate in a dose- and time-related fashion, which mirrored the respective prototypical serum cocaine CTPs. After the absorption phase, the serum cocaine CTP of PO cocaine paralleled that of IV cocaine. The duration of action for PO cocaine was longer than that for IV cocaine owing to its larger mean residence time. The active metabolite, norcocaine, was not detected after IV but after PO cocaine administration. The value of F was 4.66% which was significantly lower than the values of Fsrr (13.67%) and Frr (32.63%). Furthermore, the concentration-effect relations for the reinforcement rate revealed that PO cocaine was more potent than IV cocaine. Conclusions: Oral cocaine is more effective behaviorally than from predictions made in terms of its PK. The differences in active metabolite profiles as well as the rate and extent of acute tolerance for IV versus PO cocaine may account for the greater potency observed for oral cocaine.
Revue / Journal Title
Psychopharmacologia ISSN 0033-3158 CODEN PSYPAG
Source / Source
1999, vol. 144, no4, pp. 323-332 (46 ref.)

 

[LuxEtVeritas]

likely of interest as well:

http://jpet.aspetjournals.org/cgi/content/full/295/2/634

 

[LuxEtVeritas]

Murphy please hit up the full text of this one (posted the abstract two posts above):

Cocaine pharmacodynamics after intravenous and oral administration in rats: relation to pharmacokinetics
Journal Psychopharmacology
Publisher Springer Berlin / Heidelberg
ISSN 0033-3158 (Print) 1432-2072 (Online)
Issue Volume 144, Number 4 / June, 1999
Category Original Investigation
DOI 10.1007/s002130051014
Pages 323-332
Subject Collection Biomedical and Life Sciences
SpringerLink Date Monday, June 21, 1999

 

[LuxEtVeritas]

also note the direct transport to the brain via IN albeit small likely accounts for user preference for the quickness of fix and a higher level of perceived euphoria overall

 

[LuxEtVeritas]

There isn't a 1st pass metabolism of cocaine as the enzyme responsible (plasma pseudoesterase) as the name implies, isn't exclusively situated in the liver.

The methyl ester isn't hydrolysed that quickly, even in 0.1M HCl at 37'C - most gets absorbed before that happens. The short half life (via any route - obviously a clue!) is due to the aforementioned plasma pseudoesterases

so a BChE inhibitor would have profound effect on potency and half-life?

anyone know drawbacks to specific BChE-I?

 

[Hammilton]

By BChE you mean butyrylcholinesterase?

isn't this suxamethonium stuff? Scary.

 

[LuxEtVeritas]

^ one potential application:

Neurochem Res. 2008 May;33(5):745-53. Epub 2007 Nov 6.Click here to read Links
Kinetics of human serum butyrylcholinesterase inhibition by a novel experimental Alzheimer therapeutic, dihydrobenzodioxepine cymserine.
Kamal MA, Klein P, Luo W, Li Y, Holloway HW, Tweedie D, Greig NH.

Enzymoics, 7 Peterlee Pl., Hebersham, NSW 2770, Australia. [email protected]

Cholinergic loss is the single most replicated neurotransmitter deficiency in Alzheimer's disease (AD) and has led to the use of acetylcholinesterase inhibitors (AChE-Is) and unselective cholinesterase inhibitors (ChE-Is) as the mainstay of treatment. AChE-Is and ChE-Is, however, induce dose-limiting adverse effects. Recent studies indicate that selective butyrylcholinesterase inhibitors (BuChE-Is) elevate acetylcholine (ACh) in brain, augment long-term potentiation, and improve cognitive performance in rodents without the classic adverse actions of AChE-Is and ChE-Is. BuChE-Is thereby represent a new strategy to ameliorate AD, particularly since AChE activity is depleted in AD brain, in line with ACh levels, whereas BuChE activity is elevated. Our studies have focused on the design and development of cymserine analogues to induce selective time-dependent brain BuChE inhibition, and on the application of innovative and quantitative enzyme kinetic analyses to aid selection of drug candidates. The quantitative interaction of the novel inhibitor, dihydrobenzodioxepine cymserine (DHBDC), with human BuChE was characterized. DHBDC demonstrated potent concentration-dependent binding with BuChE. The IC(50) and specific new kinetic constants, such as K(T50), P(PC), K(T1/2) and R(I), were determined at dual substrate concentrations of 0.10 and 0.60 mM butyrylthiocholine and reaction times, and are likely attainable in humans. Other classical kinetic parameters such as K(ia), K(ma), V(ma) and V(mi) were also determined. In synopsis, DHBDC proved to be a highly potent competitive inhibitor of human BuChE in comparison to its structural analogue, cymserine, and represents an interesting drug candidate for AD

 

[Hammilton]

I would still be afraid to take it!!

it is a really cool idea though- that sounds like it'd be a pretty effective way to increase cognition.

 

[negrogesic]

A number of years ago I took ~800mg of some very high quality cocaine orally, and obviously, at this dose, it was quite effective. To me, it seemed equivalent to maybe 150mg IV, but this is a very rough estimate as these routes cannot be accurately compared.

Also, how active is norcocaine?

 

[MurphyClox]

There isn't a 1st pass metabolism of cocaine as the enzyme responsible (plasma pseudoesterase) as the name implies, isn't exclusively situated in the liver.[1]

The methyl ester isn't hydrolysed that quickly, even in 0.1M HCl at 37'C - most gets absorbed before that happens.[2] The short half life (via any route - obviously a clue!) is due to the aforementioned plasma pseudoesterases

[1] Yo, this explains it to me. That was the answer i was looking for (...somehow). Thx!

[2] Totally agreed. The second ester is by far more unstable. Methyl esters can stand A LOT of harsh conditions...

 

[LuxEtVeritas]

is the actual absolute oral bioavailability ~5% from poor absorption form the gut?

norcoke is soundly active:

Psychopharmacology (Berl). 2001 Jan;153(3):341-52.Click here to read Links
Contribution of the active metabolite, norcocaine, to cocaine's effects after intravenous and oral administration in rats: pharmacodynamics.
Wang Q, Simpao A, Sun L, Falk JL, Lau CE.

Department of Psychology, Rutgers, The State University of New Jersey, Piscataway 08854-8020, USA.

RATIONALE: Oral cocaine is more effective than IV cocaine by pharmacokinetic and pharmacodynamic analysis. One explanation is involvement of the active metabolite, norcocaine, in cocaine's effects. OBJECTIVES: To evaluate norcocaine's contribution to oral cocaine's effects, norcocaine's effects as a parent compound were determined and compared to those of cocaine using a differential reinforcement of low rate (DRL 45-s) schedule and spontaneous activity (large and small movements) after IV and PO routes of administration. METHODS: The effects of cocaine and norcocaine on DRL performance (shorter-response and reinforcement rates) and spontaneous activity were investigated in 3-h sessions. The changes in effects across time (effect-time profiles) and dose-response curves (DRCs) were constructed to evaluate the duration of action and potency (ED50) of both drugs. RESULTS: Under the DRL 45-s schedule, effect-time profiles showed both drugs via the two routes of administration significantly increasing and decreasing shorter-response rates and reinforcement rates, respectively. However, cocaine produced greater effects on shorterresponse rates than norcocaine, while both drugs produced comparable effects on reinforcement rates. For spontaneous activity, although IV cocaine, PO cocaine, and PO norcocaine dose- and time-dependently increased spontaneous activity, cocaine's effects were more profound than those of norcocaine. Effect-time profiles revealed that the duration of drug action was a function of dose, route, and behavioral paradigm used. According to ED50 values, IV cocaine was more effective than PO cocaine; however, PO cocaine was more effective than IV cocaine as judged by ED50 values corrected for absolute oral bioavailability. CONCLUSIONS: Norcocaine's contribution to oral cocaine's effects on DRL performance is evident. Other mechanism(s), such as a greater acute tolerance to IV cocaine's effects than to PO cocaine's effects, can be excluded.

 

[LuxEtVeritas]

I would still be afraid to take it!!

it is a really cool idea though- that sounds like it'd be a pretty effective way to increase cognition.

i am not sure this would be a sound route for enhancing cognition in otherwise health, 'normal' subjects....though if someone wishes to elaborate why they think otherwise please do...

 

[jammon]

I thought that 50 mg of coke taken orally would feel like say a 20 mg adderall pill for 8 hrs, maybe with some alcohol?... Yeah little more would be needed than if taken nasally but still.....

 

[sekio]

Cocaine being a reuptake inhibitor won't/shouldn't feel at all like amphetamine. & it sure as shit shouldn't last for 8 hours

 

[jammon]

I'll dissolve 60 mg of good stuff in some cold coke or even beter, a hot coca tea.. and drink it. I'm expecting 1 hr of a fine coke-ish feeling

oh man, a coca tea with extra coke in it, that quantity should feel so smooth and freeze warmly both mouth and throat