• N&PD Moderators: Skorpio

medication metabolism question part II

Deleted member 137730

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I have posted on this topic before, and the moderators claimed what im saying to be impossible which i understand, but its not and i need answers... please dont close this.

anyway to the point. I took a single 20 mg of aripiprazole around 2.5 months ago. I am 100% sure it is still in my system and i dont understand why this is possible.

I know this because amphetamine and methylphenidate are completely inhibited at ANY dosage i take along with all other dopamine active drugs. I can also feel the difference its obvious, so yes its in my system.

With a half life of 96 hours ( dehydroaripiprazole) it should still be out. Abilify is active at doses as low as .25 mg which can cause upwards of 50% receptor occupancy.

I am taking suboxone concurently which is a cypd inhibitor but not a major one, idk if this contributes.

Also im wondering if perhaps i have cypd genetic deletion that apparently some caucasians have.

any thoughts to help me out, i really need this out of my system and dont understand this.

thanks bben.
 
I am never one to minimize the subjective experiences of patients. Yes, honestly, it is would seem extremely unlikely that a single dose of abilify would result in inability to experience the effects of MPH or D-AMP. More info is needed. Do you experience measurable hypertension from mph amp?
 
not when on abilify, its like popping skittles. i took 100mg dextroamphetamine and i never take it and it didnt do shit. took it right out of the prescription bottle.

its clearly in my system, but why so long...
 
I am 100% sure it is still in my system and i dont understand why this is possible.
...because it isn't possible. You are confusing subjective feelings with objective laboratory analytics! It's highly unlikely that after a single (!) dose 10 weeks ago any fraction of the drug is left in your system. Even without any metabolzation (...purely fictional case), the drug would be extrected unchanged to some extend via the urine (1% ) and feces (18% ).

Aripiprazole is metabolized primarily by dehydrogenation, hydroxylation (CYP3A4 & CYP2D6) and N-dealkylation (CYP3A4). Aripiprazole is the predominant drug moiety in the systemic circulation. At steady state, dehydro-aripiprazole, the active metabolite, represents about 40% of aripiprazole AUC in plasma. Approximately 8% of Caucasians lack the capacity to metabolize CYP2D6 substrates and are classified as poor metabolizers (PM), whereas the rest are extensive metabolizers (EM). PMs have about an 80% increase in aripiprazole exposure and about a 30% decrease in exposure to the active metabolite compared to EMs, resulting in about a 60% higher exposure to the total active moieties from a given dose of aripiprazole compared to EMs. Coadministration of abilify with known inhibitors of CYP2D6 (eg. quinidine) in EMs, results in a 112% increase in aripiprazole plasma exposure, and dosing adjustment is needed. The mean elimination half-lives are about 75 hours and 146 hours for aripiprazole in EMs and PMs, respectively. Aripiprazole does not inhibit or induce the CYP2D6 pathway.



The following could be interesting for you:

"Evaluation of subjective effects of aripiprazole and methamphetamine in methamphetamine-dependent volunteers."
International Journal of Neuropsychopharmacology (2008 ), 11(8 ): 1037-1045:
Abstract
A variety of neuropharmacol. strategies are being pursued in the search for an effective treatment for methamphetamine (Meth) addiction. In this study, we investigated the safety and potential efficacy of aripiprazole, an antipsychotic agent acting on both dopamine and serotonin systems. We conducted a double-blind in-patient clin. pharmacol. study to assess potential interactions between i.v. Meth (15 mg and 30 mg) and oral aripiprazole (15 mg). In addn., the effects of aripiprazole treatment on abstinence-related craving and cue-induced craving were evaluated. Participants included non-treatment-seeking, Meth-dependent patients (n=16), aged 18-45 yr, currently using Meth. Following baseline Meth dosing (15 mg and 30 mg), participants received 2 wk treatment with aripiprazole (n=8 ) or placebo (n=8 ). Participants then completed cue exposure sessions using neutral and Meth-related cues. Meth dosing (15 mg and 30 mg) was then repeated. Aripiprazole treatment had no effect on cue-induced Meth craving, or on daily baseline craving assessed over the course of medication treatment, although aripiprazole treatment was assocd. with increased craving independent of Meth dosing. Aripiprazole treatment was assocd. with significantly higher ratings on Addiction Research Center Inventory (ARCI) subscales reflecting euphoria and amphetamine-like effects following Meth dosing. Aripiprazole treatment was also assocd. with significant redns. in ratings of bad effects' and redns. on the ARCI subscale for sedation effects following Meth dosing. Aripiprazole treatment reduced the increase in systolic blood pressure following Meth dosing, but had no other effects on cardiovascular responses to Meth. Aripiprazole treatment did not alter the pharmacokinetics of Meth.
These findings indicate that aripiprazole treatment appears to be safe in volunteers with Meth dependence, although the finding that aripiprazole increased some of the rewarding and stimulatory effects produced by acute Meth suggests that 15 mg aripiprazole is unlikely to be efficacious for the treatment of Meth dependence. Further research with lower doses of aripiprazole, possibly using study designs aimed at evaluating efficacy for relapse prevention, are needed before ruling out aripiprazole as a treatment for Meth dependence.​

"Pharmacokinetics of domestic aripiprazole after single and multiple dosing in healthy volunteers."
Zhongguo Yaoxue Zazhi (Beijing, China) (2007), 42(24): 1892-1895
Abstract
A HPLC-UV method was developed for determing aripiprazole in human plasma, and the pharmacokinetic profiles of domestic Aripiprazole tablets in healthy volunteers were studied. A single and multiple oral doses of domestic aripiprazole were given to 12 and 14 healthy volunteers resp. Aripiprazole concentrations in plasma were determined by HPLC method. The pharmacokinetic parameters of aripiprazole were obtained with statistical analysis by DAS1.0.
The main pharmacokinetic parameters of a single dose of aripiprazole were as followed: ρmax was (108.4 22.5) µg/L-1, tmax was (4.9 0.7) h, AUC0-192h was (5748.2 874.5) µg/h/L-1, t1/2β was (107.4 29.0) h, CL/F was (3.56 0.55) L/h-1 and V/F was (261.6 49.1) L.
In multiple dose study, aripiprazole were given to the healthy volunteers for 14 d to achieve steady state, the peak concentrations of (480.3 126.2) µg/L-1 and was reached at (4.0 0.9) h after the last administration in steady state. AUC0-360h was (38166.6 13241.2) µg/h/L-1, t1/2β was (91.0 21.1) h, CL/F was (0.62 0.36) L/h-1 and V/F was (60.9 43.7) L. The concentration-time curves of aripiprazole were described by a two-compartment open model. And it offered necessary information for clinical use of aripiprazole in Chinese.​
Note: This data is comparable to data obtained in caucasian patients.

"Pharmacokinetics of aripiprazole, a new antipsychotic, following oral dosing in healthy adult Japanese volunteers: influence of CYP2D6 polymorphism."
Drug Metabolism and Pharmacokinetics (2007), 22(5): 358-366
Abstract
We investigated the pharmacokinetics (PK) of aripiprazole, a newly developed antipsychotic, and its active metabolite in healthy Japanese, and the influence of CYP2D6 polymorphism on the PK of aripiprazole. Following a single oral 6 mg dose, the mean Cmax, tmax, and t1/2,z (terminal phase half life) of aripiprazole were 31.0 ng/mL, 3.6 h, and 61.0 h, resp. The t1/2,z in CYP2D6 IM subjects (75.2 h) was significantly (p < 0.01) longer than that in CYP2D6 EM subjects (45.8 h), and the systemic clearance of IM subjects was approx. 60% that of EM subjects. The PK in one subject with the CYP2D6*41 homozygote was similar to that of IM subjects. In repeated oral administration, plasma concns. of aripiprazole and active metabolite both reached a steady state by Day 14. The half-life of aripiprazole following repeated administration was similar to that following single administration, suggesting that pharmacokinetics was const. during 14-day administration. Our investigations revealed that there is no clear ethnic difference between Japanese and Western subjects in terms of mean plasma PK, while the CYP2D6*10 allele distinctive to Asian populations influences the PK of aripiprazole. Moreover, our observations suggest that the CYP2D6*41 allele significantly affects drug-metabolizing activity.​
Note: IM = intermediate metabolizer, EM = extensive metabolizer


Further detailed information here: http://www.druglib.com/druginfo/abilify/description_pharmacology/
 
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I know abilify is protein bound and barely excreted from urine at all. I mean the fact i took a high dose while taking suboxone which is a strong cypd inhbitor and having maybe a cypd genetic deletion has clearly resulted in it somehow staying in my system.

i def appreciate those abstracts, i had read all of them but one. Thanks for taking time to respond to my question and the good objective insight provided.
 
not when on abilify, its like popping skittles. i took 100mg dextroamphetamine and i never take it and it didnt do shit. took it right out of the prescription bottle.

its clearly in my system, but why so long...

Hold on........so this is not a single dose of abilify? Are you continuing to take the drug? What was the drug prescribed for?
 
It was a single dose i guess 2 or maybe a bit more months ago. i may have taken jus like a small .25 amount 1 month ago. Other than that i took nothing but suboxone with it. i took it for mood stability and some prodromal signs.

Its simply not leaving my system and driving me NUTS!
 
I know abilify is protein bound and barely excreted from urine at all.
Correct, but nonetheless are 18 % excreted unchanged via the feces. In other words: Even without any metabolism taking place (again, that is purely fictional, because 2 of 3 metabolic pathways are done by CYP3A4!*), you will simply shit out ca. one fifth of the dose. Hence, the reason for your physiological resp. psychological reaction must be a different one!

No need to "off yourself", buddy. Seriously! I can understand your desire to solve this riddle, but it's time to look for alternative explanations. Otherwise you're running in circles, I'm afraid...


* Edit:
I emphasized this, because CYP3A4 has such an outstanding importance that you would be probably dead if this enzyme would be inactive for a longer time.
 
Correct, but nonetheless are 18 % excreted unchanged via the feces. In other words: Even without any metabolism taking place (again, that is purely fictional, because 2 of 3 metabolic pathways are done by CYP3A4!*), you will simply shit out ca. one fifth of the dose. Hence, the reason for your physiological resp. psychological reaction must be a different one!

No need to "off yourself", buddy. Seriously! I can understand your desire to solve this riddle, but it's time to look for alternative explanations. Otherwise you're running in circles, I'm afraid...


* Edit:
I emphasized this, because CYP3A4 has such an outstanding importance that you would be probably dead if this enzyme would be inactive for a longer time.

18% isnt 100%. id love to kno the rate of unchanged urine metabolization if u got it. Also suboxone is a strong inhibitor of cyp 3a4 so assuming i have a genetic deletion of cypd 2d6 abilify would be metabolized exclusively by an inhibited enzyme. and lets assume i have weak 3a4 enzymes to begin with this could take a long ass time.

obviously its still in my system if my dopamine system is totally blocked. the question is why and how do i induce faster metabolization of it.
 
...errr, the 18%-value was derived after a single dose and counts for a normal metabolizing individual. With every dump you do you will excrete a certain amount of the drug, hence eliminating it from your system over time. It's not like your body excretes exactly 18% and then stops this way of elimination.

Apart from this is CYP3A4-inhibition by buprenorphine not quantitative!!! Take, just as one example, this, Sir:

"Interaction of buprenorphine and its metabolite norbuprenorphine with cytochromes P450 in vitro."
Drug Metabolism and Disposition (2003), 31(6): 768-772:
Buprenorphine is a thebaine derivative used in the treatment of heroin and other opiate addictions. In this study, the selective probe reactions for each of the major hepatic cytochromes P450 (P450s) were used to evaluate the effect of buprenorphine and its main metabolite norbuprenorphine on the activity of these P450s. The index reactions used were CYP1A2 (phenacetin O-deethylation), CYP2A6 (coumarin 7-hydroxylation), CYP2C9 (diclofenac 4′-hydroxylation), CYP2C19 (omeprazole 5-hydrxoylation), CYP2D6 (dextromethorphan O-demethylation), CYP2B6 (7-ethoxy-4-trifluoromethyl-coumarin 7-deethylation), CYP2E1 (chlorzoxazone 6-hydroxylation), and CYP3A4 (omeprazole sulfoxidation). Buprenorphine exhibited potent, competitive inhibition of CYP2D6 (Ki 10 ± 2 μM and 1.8 ± 0.2 μM) and CYP3A4 (Ki 40 ± 1.6 μM and 19 ± 1.2 μM) in microsomes from human liver and cDNA-expressing lymphoblasts, respectively. Compared with buprenorphine, norbuprenorphine demonstrated a lower inhibitory potency with CYP2D6 (22.4% inhibition at 20 μM norbuprenorphine) and CYP3A4 (13.6% inhibition at 20 μM) in microsomes from human cDNA-expressing lymphoblast cells. Furthermore, buprenorphine was shown to be a substrate of CYP2D6 (Km = 600 μM; Vmax = 0.40 nmol/min/mg protein) and CYP3A4 (Km = 36 μM; Vmax = 0.19 nmol/min/mg protein). The present in vitro study suggests that buprenorphine and its major metabolite norbuprenorphine are inhibitors of CYP2D6 and CYP3A4; however, at therapeutic concentrations they are not predicted to cause potentially clinically important drug interactions with other drugs metabolized by major hepatic P450s.

That last part was marked red by me to emphasize the important detail. I would conclude the same, considering a Ki in the 2-digit µM-range (which isn't extremely potent).
 
...errr, the 18%-value was derived after a single dose and counts for a normal metabolizing individual. With every dump you do you will excrete a certain amount of the drug, hence eliminating it from your system over time. It's not like your body excretes exactly 18% and then stops this way of elimination.

Apart from this is CYP3A4-inhibition by buprenorphine not quantitative!!! Take, just as one example, this, Sir:

"Interaction of buprenorphine and its metabolite norbuprenorphine with cytochromes P450 in vitro."
Drug Metabolism and Disposition (2003), 31(6): 768-772:
Buprenorphine is a thebaine derivative used in the treatment of heroin and other opiate addictions. In this study, the selective probe reactions for each of the major hepatic cytochromes P450 (P450s) were used to evaluate the effect of buprenorphine and its main metabolite norbuprenorphine on the activity of these P450s. The index reactions used were CYP1A2 (phenacetin O-deethylation), CYP2A6 (coumarin 7-hydroxylation), CYP2C9 (diclofenac 4′-hydroxylation), CYP2C19 (omeprazole 5-hydrxoylation), CYP2D6 (dextromethorphan O-demethylation), CYP2B6 (7-ethoxy-4-trifluoromethyl-coumarin 7-deethylation), CYP2E1 (chlorzoxazone 6-hydroxylation), and CYP3A4 (omeprazole sulfoxidation). Buprenorphine exhibited potent, competitive inhibition of CYP2D6 (Ki 10 ± 2 μM and 1.8 ± 0.2 μM) and CYP3A4 (Ki 40 ± 1.6 μM and 19 ± 1.2 μM) in microsomes from human liver and cDNA-expressing lymphoblasts, respectively. Compared with buprenorphine, norbuprenorphine demonstrated a lower inhibitory potency with CYP2D6 (22.4% inhibition at 20 μM norbuprenorphine) and CYP3A4 (13.6% inhibition at 20 μM) in microsomes from human cDNA-expressing lymphoblast cells. Furthermore, buprenorphine was shown to be a substrate of CYP2D6 (Km = 600 μM; Vmax = 0.40 nmol/min/mg protein) and CYP3A4 (Km = 36 μM; Vmax = 0.19 nmol/min/mg protein). The present in vitro study suggests that buprenorphine and its major metabolite norbuprenorphine are inhibitors of CYP2D6 and CYP3A4; however, at therapeutic concentrations they are not predicted to cause potentially clinically important drug interactions with other drugs metabolized by major hepatic P450s.

That last part was marked red by me to emphasize the important detail. I would conclude the same, considering a Ki in the 2-digit µM-range (which isn't extremely potent).

yes im glad ive got you responding, keep it up!!!

I have found other studies that say while predicted not too, in reality it prob does inhibit some to alot, which is why it says its not PREDICTED too, that studies outdated as shit haha. keep it comin though. and im pretty sure its 18% total through feces and the rest goes through good ole cypd metabolism.


i REALLY WISH it were not possible i am goin crazy!!!
 
Look you are going to drive yourself crazy trying to pinpoint the possible mechanism, because you will never find an answer. Unfortunately your case would be given the NOS/Idio label (not other wise specific, med speak for 'i have no fucking clue'). I am sorry, legitimately....
 
Get your friends to measure your blood pressure and pulse in a double-blind study. That's the only thing I can think of.
 
Look you are going to drive yourself crazy trying to pinpoint the possible mechanism, because you will never find an answer. Unfortunately your case would be given the NOS/Idio label (not other wise specific, med speak for 'i have no fucking clue'). I am sorry, legitimately....

yes well i still have the problem dude, the abilify is not metabolizing out at all..... its been months now and its still blocking everything.....

its fucked up . im getting my doc to request a cypd enzyme test even though its very expensive i cant live foreever like this.
 
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