Nortriptyline (brand name “Pamelor”) is considered the chief pharmacologically active metabolite of the chemical amitriptyline, a tricyclic antidepressant derived from dibenzocycloheptene. Formation of nortriptyline occurs upon hepatic oxidative N-demethylation of amitriptyline via CYP2D6 and CYP2C19 isoenzymes. In the early 1960s, researchers realized a significant portion of amitriptyline’s antidepressant effects resulted from the formation of its nortriptyline metabolites.
As of 1964, the chemical nortriptyline had been isolated and received FDA approval as a standalone treatment for major depressive disorder and childhood nocturnal enuresis (bedwetting). Nortriptyline has also been investigated as an off-label treatment for chronic fatigue syndrome, migraine headaches, and neuropathic pain. It is believed to function as a reuptake inhibitor of norepinephrine and serotonin, as well as antagonize histamine (H1), muscarinic acetylcholine (mACh), and adrenergic (A1) receptor sites.
This mechanism of action alleviates symptoms of depression, likely with greater potency than its parent drug (amitriptyline); largely due to its status as a secondary (rather than a tertiary) amine. Though many individuals respond well to nortriptyline, others dislike its side effects such as: blurred vision, constipation, dry mouth, urinary retention, etc. Inevitably, these side effects may prompt a user to discontinue treatment, wondering how long it takes to get nortriptyline out of their system.
How long does Nortriptyline stay in your system?
Upon complete discontinuation of this drug, you may notice the emergence of severe nortriptyline withdrawal symptoms. You may also notice that side effects you experienced while taking nortriptyline continue to linger for days after your final dose. This may lead you to question whether nortriptyline is still somehow in systemic circulation.
To accurately calculate how long nortriptyline is likely to remain in your plasma following your last dose, it is necessary to consider its elimination half-life. The elimination half-life of nortriptyline is highly variable, cited between the range of 16 and 90 hours post-discontinuation. Some speculate that the mean elimination half-life may be around 25 hours; this indicates that it’ll usually take over one day to eliminate 50% of a circulating dose.
Considering the wide-ranging span of its elimination half-life, we can estimate that nortriptyline could be eliminated from your system in as quickly as 3.67 days after discontinuation, but may take as long as 20.63 days. Based on the speculated average half-life of 25 hours in healthy adults, most users will have cleared the drug from their systems in around 5.73 days (just under 6 days).
However, just because nortriptyline may have been eliminated from your system, does not necessarily mean that its active metabolite 10-hydroxy-nortiptyline (10-OH-NT) will have been eliminated. The 10-hydroxy-nortriptyline metabolite has an elimination half-life ~1 hour longer than its parent (nortriptyline). Nonetheless, it should be out of your system within ~6 hours of the parent (nortriptyline). For most healthy adults, nortriptyline will be eliminated from the plasma between 5 and 7 days post-discontinuation.
- Source: http://www.ncbi.nlm.nih.gov/pubmed/7248140
Variables that influence how long Nortriptyline stays in your system
The duration you can expect nortriptyline to remain in systemic circulation upon cessation is determined by an array of interindividual variables. Perhaps the most pronounced variable that influences elimination speed is the allelic (genetic) expression of CYP2D6; the isoenzyme responsible for a majority of nortriptyline metabolism. Other factors to consider that influence elimination speed include: individual attributes, dosage, term of administration, and co-administered drugs.
There is robust evidence to suggest that allelic expression of CYP2D6 influences the speed at which nortriptyline is metabolized, which ultimately dictates its half-life. Individuals that are considered “rapid metabolizers” of nortriptyline will metabolize it quickly and also clear it from their systems quicker than average. Conversely, those that are considered “poor metabolizers” will have a tough time eliminating nortriptyline efficiently from their plasma, leading to a protracted half-life.
- Ultrarapid metabolizers: A small percentage of the population (1-2%) carries multiple copies of functional CYP2D6 alleles (e.g. *1/*1xN). These individuals are considered “ultrarapid metabolizers” in that an ingested dose of nortriptyline is quickly broken down and eliminated from the plasma. These individuals often fail to exhibit therapeutic plasma concentrations of the drug and usually don’t respond well to nortriptyline treatment because it plasma levels cannot be maintained.
- Extensive metabolizers: A majority of the population (77-92%) of users are considered “extensive metabolizers” of nortriptyline. These individuals are carrying multiple alleles with either: full or reduced function OR one full function plus one non-functional or one reduced function allele. If you are considered an extensive metabolizer of nortriptyline, you should clear it from systemic circulation in an average amount of time, but not as fast as an ultrarapid metabolizer.
- Intermediate metabolizers: A lesser percentage (2-11%) of nortriptyline users are classified as “intermediate metabolizers.” Intermediate metabolizers carry one reduced function plus one non-functional CYP2D6 allele. As a result, they often exhibit elevated plasma concentrations of nortriptyline when administered at standard doses and a prolonged elimination half-life. For this reason, dosage reductions are often recommended by professionals. If an intermediate metabolizer takes a lower dose, elimination half-life may not be subject to as substantial of an increase as at standard or high doses.
- Poor metabolizers: A final subset of nortriptyline users are considered “poor metabolizers.” These individuals carry no functional CYP2D6 alleles and therefore are unable to effectively metabolize nortriptyline. Poor metabolizers taking standard doses of nortriptyline are prone to significant side effects due to elevations in plasma concentrations, as well as a protracted half-life. If you are a CYP2D6 poor metabolizer, expect to retain nortriptyline for a much longer duration than usual.
It should be noted that there is some evidence that specific diplotypes matter in regards to elimination. Two individuals considered “extensive metabolizers” may eliminate nortriptyline at different speeds as a result of respective diplotypes. One study found that individuals homozygous for CYP2D6*10 exhibited longer elimination half-lives of nortriptyline compared to those homozygous for CYP2D6*1.
If you aren’t sure about your particular phenotype, consider undergoing a genetic analysis such as that provided by “GeneSight.” Results from this testing can be used to determine how quickly you metabolize certain drugs based on your genes, which in turn regulate the isoenzyme function within your liver. Certain alleles reduce CYP2D6 function, while others decrease it – both of which have a major impact upon nortriptyline’s elimination half-life.
- Source: http://www.ncbi.nlm.nih.gov/pubmed/9797795
- Source: http://www.ncbi.nlm.nih.gov/pubmed/23486447
Although genetic expression of CYP2D6 alleles has the greatest influence upon nortriptyline elimination, other factors also influence elimination speed. Even if two individuals were considered heterozygous for CYP2D6*1 and simultaneously administered a single 50 mg dose of nortriptyline, one user would eliminate the drug quicker (even if just marginally) than the other individual. These differences can be chalked up to interindividual factors such as: the user’s age, body mass, hepatic function, metabolic rate, and renal function.
Age: Studies have suggested that single oral doses of nortriptyline may be metabolized and eliminated at a slower rate among elderly individuals (over the age of 65) compared to younger adults. Elderly individuals appear to exhibit greater plasma concentrations of nortriptyline, and elimination half-life is prolonged. This shouldn’t be much of a surprise as similar pharmacokinetic differences appear for related chemicals such as amitriptyline.
Possible reasons for prolonged elimination half-life of nortriptyline among elderly (compared to younger adults) include: diminishing hepatic function, decreased renal function, altered levels of plasma proteins, and distributional differences of nortriptyline (and its metabolites) throughout the body. Specifically, the volume of nortriptyline distribution is likely to be greater among elderly, thereby increasing elimination time.
- Source: http://www.ncbi.nlm.nih.gov/pubmed/6994983
Body mass + Fat (%): A person’s body mass and/or fat percentage may dictate how long nortriptyline (and its metabolites) remain in systemic circulation upon discontinuation. Individuals with a high BMI and/or fat percentage may be likely to retain nortriptyline for a longer duration than those with lower BMIs and/or body fat. This is largely due to the fact that nortriptyline is a highly lipophilic drug, meaning that it is soluble in fat.
Someone with a high percentage of body fat will have a greater quantity of adipose tissue for nortriptyline (and metabolite) accumulation. On the other hand, someone with a low percentage of body fat won’t have as much adipose tissue, thereby preventing significant accumulation and promoting efficient elimination of nortriptyline. The exact degree to which body fat influences elimination half-life of nortriptyline isn’t fully elucidated, but it is suspected to increase it as a result of nortriptyline’s lipophilicity.
Furthermore, it is necessary to consider that obese individuals often exhibit differences in levels of plasma proteins – which in turn affects drug distribution, as well as downregulated renal function compared to non-obese counterparts. Though the difference in elimination half-life of nortriptyline between obese and non-obese subjects may not be clinically significant, it may differ slightly as a result of body fat percentage and/or overall size.
- Source: http://www.ncbi.nlm.nih.gov/pubmed/3042569
- Source: http://www.ncbi.nlm.nih.gov/pubmed/11020136
Hepatic function: Since nortriptyline is metabolized primarily by CYP2D6 isoenzymes in the liver, hepatic function is likely to affect its elimination half-life. Individuals with varying forms of hepatic impairment are likely to experience decreased functionality of hepatic isoenzymes such as CYP2D6, leading to compromised metabolism of nortriptyline. Compromised metabolism is known to increase plasma concentrations and prolong plasma elimination.
The degree of hepatic impairment generally dictates how long nortriptyline is likely to remain in a user’s system. The greater the level of impairment, the poorer the CYP2D6 isoenzyme metabolism of nortriptyline, and ultimately the longer it will be retained in systemic circulation. In other words, someone with severe hepatic impairment is likely to retain nortriptyline for a longer duration post-discontinuation than someone with mild hepatic impairment.
That said, two individuals with the exact same mild degree of hepatic impairment may retain nortriptyline for different durations based on their underlying CYP2D6 isoenzyme expression. The effect of mild hepatic impairment on an intermediate metabolizer may be significant enough to make him/her exhibit the metabolism of a “poor metabolizer,” whereas the effect of mild hepatic impairment upon an extensive metabolizer may not be as noticeable. In any regard, hepatic impairment will likely increase elimination half-life of nortriptyline, even if to a minor extent.
Metabolic rate: Some speculate that a user’s BMR (basal metabolic rate) may affect how long nortriptyline remains in systemic circulation. Though when experts refer to drug metabolism, they first (and rightfully so) consider CYP450 isoenzyme expression for hepatically metabolized drugs, a user’s basal metabolic rate may affect how quickly the drug is eliminated from the plasma. There is some evidence to suggest that individuals with a high BMR may clear nortriptyline (and other drugs) from systemic circulation quicker than those with lower BMRs.
The higher your BMR, the more energy your body is burning at rest, and arguably the more primed your physiology will be to metabolize and eliminate exogenous substances (such as nortriptyline). Oppositely, the lower your BMR, the less energy your body is burning as rest, and likely the less readily your physiology will clear exogenous substances from circulation. Therefore, it is possible (and likely) that BMR has a slight influence on nortriptyline elimination.
Renal function: Individuals with compromised renal function often exhibit prolonged elimination of nortriptyline (and its metabolites) compared to those with normative renal function. In cases of renal impairment, the efficiency of nortriptyline metabolite excretion is reduced. As a result, nortriptyline metabolites may accumulate within various renal pathways, increasing likelihood of reabsorption and recirculation prior to excretion.
Studies suggest that although mild cases of renal impairment are unlikely to clinically affect nortriptyline metabolite elimination, severe forms of renal impairment (e.g. chronic renal failure) significantly reduce nortriptyline clearance and elimination. However, in most cases of renal dysfunction, pharmacokinetic properties of nortriptyline are not significantly altered. If you have severe renal impairment, expect to retain nortriptyline in your system for a longer-than-average duration.
- Source: http://www.ncbi.nlm.nih.gov/pubmed/7105623
- Source: http://www.ncbi.nlm.nih.gov/pubmed/7248140
Urinary pH: One study analyzed the effect of urinary pH on the excretion of amitriptyline and its metabolites. The study discovered that acidification of a user’s urinary pH can increase renal excretion of nortriptyline (amitriptyline’s chief metabolite) by nearly 1000-fold. This indicates that nortriptyline is acid labile and that the acidity of your urine is likely to affect how long it remains in your system, particularly renal pathways, prior to excretion.
It is likely that individuals with highly alkaline urine retain nortriptyline (and its metabolites) for a longer duration than those with highly acidic urine. The pH of your urine will be largely influenced by your dietary intake. If you eat foods that increase acidity of your urine, expect a more efficient and quicker elimination of nortriptyline from your system. If you are eating a highly alkaline diet, realize that efficiency of nortriptyline excretion may be reduced.
- Source: http://www.ncbi.nlm.nih.gov/pubmed/3015809
Dosage (High vs. Low)
The dosage of nortriptyline that you were taking will likely affect how long it stays in your system. If you were to ingest a single 10 mg dose of nortriptyline, you’d likely eliminate it at a faster rate than if you ingested a 75 mg dose. This is somewhat due to the fact that at lower doses, less of a burden is placed on hepatic enzymes. It is this reason that CYP2D6 intermediate metabolizers are recommended to take lower doses; their hepatic isoenzymes cannot handle the drug as efficiently.
Upon taking a high dosage, hepatic enzymes may be overtaxed by the sheer quantity of ingested nortriptyline, leading to less efficient metabolism. A less efficient metabolism yields elevated plasma concentrations of nortriptyline (and its metabolites), leading to an increased elimination half-life. Larger doses generate a greater number of circulating metabolites and a greater volume of distribution.
The increased number of metabolites and heightened distribution suggests an increased propensity of nortriptyline metabolite accumulation in adipose tissue (fat stores). Furthermore, after the drug (and its metabolites) are eliminated from the plasma, renal excretion ensues. Renal excretion may be altered if a large dose of nortriptyline is ingested as this may decrease efficiency of clearance and increase likelihood of reabsorption prior to elimination.
A user taking a low dose will metabolize nortriptyline more efficiently, accumulate less metabolites within adipose tissues, and excrete the drug at a quicker rate. The prolonged elimination half-life of high doses is perhaps best evidenced in cases of overdose. In one case of an amitriptyline overdose, the elimination half-life of its nortriptyline metabolite was approximately 47.5 hours.
This half-life suggests that it took nearly 10.9 days to eliminate nortriptyline from plasma circulation; significantly longer than the average (of 5.73 days) in healthy adults. Therefore, we can hypothesize that an abnormally high and/or supratherapeutic dose of nortriptyline is likely to significantly increase its half-life. Dose-related increases in elimination half-life of nortriptyline may be most noticeable among poor or intermediate CYP2D6 metabolizers.
- Source: http://www.ncbi.nlm.nih.gov/pubmed/21614669
Term of administration
The term over which you’ve administered nortriptyline may affect how long it remains in your system. Individuals that have only taken nortriptyline for a day or two are unlikely to have attained steady state concentrations of the drug and plasma concentrations are likely to be lower than those of longer-term users. Medical literature suggests that it takes between 4 and 21 days to attain steady state concentrations of nortriptyline.
If you haven’t been taking nortriptyline for long enough to reach steady state levels and discontinue treatment, you’ll likely eliminate the drug from systemic circulation at a quicker pace than average. On the other hand, if you’ve been taking nortriptyline for long enough to attain steady state concentrations, your elimination half-life is likely to be longer than a single-dose or extremely short-term user. In addition, it is necessary to consider that term of administration may indirectly affect its elimination half-life by influencing the dosage that a user is taking.
As was discussed above, greater dosages equal increases in half-life. Long-term users of nortriptyline often discover that their initial dose “wears off” and/or stops working; this is due to neurophysiologic tolerance. This tolerance leads to an increase in nortriptyline dosage (or possibly multiple upward dosage titrations) to reestablish therapeutic efficacy that the lower dose initially provided.
Short-term users are unlikely to have developed tolerance to their initial starting doses, and therefore should eliminate the drug more efficiently than a lower dose user. Furthermore, a shorter-term of administration may reduce cumulative nortriptyline accumulation (along with its metabolites) in adipose tissue. For these reasons, it should be suspected that short-term users will eliminate nortriptyline faster from their systems than long-term users.
Co-administered drugs (CYP2D6 inhibitors/inducers)
If you were taking other drugs (and/or supplements) along with nortriptyline, its possible that they may have significantly altered its hepatic metabolism. Certain substances are known to interfere with hepatic pathways responsible for metabolizing nortriptyline, while others enhance function of these pathways. As you can logically guess, pathway interference leads to prolonged elimination of nortriptyline, whereas activation (or enhancement) expedites elimination.
Since nortriptyline is metabolized via CYP2D6 (cytochrome P450 2D6) isoenzyme pathways, any drugs that have an affinity for CYP2D6 will affect how long it remains in systemic circulation. Drugs classified as “CYP2D6 inhibitors” are known to downregulate CYP2D6 isoenzyme function, thereby decreasing the amount of nortriptyline that gets metabolized. Examples of such inhibitors of CYP2D6 include: Bupropion, Cinacalcet, Fluoxetine, Paroxetine, Quinidine, and Ritonavir.
Should you have co-ingested a CYP2D6 inhibitor, expect to retain nortriptyline for a longer-than-average duration after discontinuation. On the other hand, co-ingestion of a CYP2D6 inducer will enhance the metabolism of nortriptyline, leading to faster systemic elimination of nortriptyline. Examples of CYP2D6 inducers include: Dexamethasone, Glutethimide, Promethazine, and Rifampicin.
Note: The degree to which the aforementioned CYP2D6 inhibitors/inducers increase or decrease elimination half-life of nortriptyline may be subject to their respective potencies and the dosages at which they were administered.
Nortriptyline: Absorption, Metabolism, Excretion (Details)
Following oral administration of nortriptyline, it is efficiently absorbed by the gastrointestinal (GI) tract. It undergoes hepatic first-pass metabolism, facilitated chiefly by CYP2D6, a cytochrome P450 isoenzyme. CYP2D6 converts nortriptyline to its primary metabolite 10-hydroxy-nortriptyline (10-OH-NT) via hydroxylation at carbon-10.
After undergoing first-pass hepatic metabolism, nortriptyline concentrations peak in the plasma between 7 and 8.5 hours post-ingestion. Nortriptyline, as well as its 10-hydroxy-nortriptyline metabolites are then distributed throughout the body. Its oral bioavailability is estimated at 66% (+/- 21%), suggesting that retains greater bioavailability as a secondary amine than its parent drug amitriptyline, a tertiary amine.
Therapeutic responses to nortriptyline are attained when plasma concentrations are within the range of 50 and 150 ng/mL. Steady state concentrations of nortriptyline are attained between 4 and 21 days of administration. Due to its lipophilicity, it is thought that nortriptyline and its metabolites may accumulate within bodily tissues (e.g. adipose tissue) as a result of continuous long-term administration.
Once nortriptyline and its metabolites have been distributed, its plasma half-life falls within the range of 16 to 90 hours. Some research suggests that average elimination half-life of nortriptyline is around 25 hours, whereas that of its 10-hydroxy-nortriptyline metabolite is 26 hours. This suggests that elimination of nortriptyline and 10-OH-NT metabolites may take 5.96 days (nearly 6 days) post-ingestion.
However, the half-life range of 16 to 90 hours indicates that plasma elimination may occur as quickly as 3.67 days post-ingestion, but could take as long as 21 days in some users. As plasma concentrations decline, a majority of nortriptyline is subject to urinary excretion, with smaller amounts excreted via feces. Around 80% of a nortriptyline dose will appear as 10-hydroxy-nortriptyline metabolites within urinary excrement.
Most nortriptyline users can safely assume that they should be detoxified from nortriptyline (and its 10-OH-NT metabolites) within 1 to 2 weeks of their last dose. In rarer cases, it could take 3 to 4 weeks for complete excretion and detoxification from nortriptyline.
- Source: https://pubchem.ncbi.nlm.nih.gov/compound/nortriptyline
- Source: http://www.ncbi.nlm.nih.gov/pubmed/852498
Tips to clear Nortriptyline from your system
If you’ve discontinued nortriptyline, you may want to know how you can get the drug out of your system as soon as possible. That said, you may want to avoid rapid elimination due to the fact that a shorter half-life often increases severity of discontinuation effects. If you’ve been nortriptyline-free for awhile now and want to ensure that you’re detoxified, below are some tips. Keep in mind that prior to implementing any of these tips, it is necessary to verify safety and alleged efficacy with a medical professional.
- Activated charcoal: Arguably one of the most effective supplements for general detoxification is that of activated charcoal. Activated charcoal binds to unmetabolized drugs, as well as endotoxins that they may have generated while in systemic circulation. Studies have shown that repeated administration of activated charcoal increases the elimination rate of nortriptyline via interrupting its enterohepatic (liver) and enteroenteric (intestinal) circulation (Source: http://www.ncbi.nlm.nih.gov/pubmed/3015809)
- Calcium-d-glucarate: Most of a nortriptyline dosage is excreted from the body via renal pathways. The supplement calcium-d-glucarate is known to act as a beta-glucuronidase inhibitor, essentially forcing the clearance of molecules within detoxification pathways. Think of this supplement as aiding in renal excretion, perhaps expediting the efficiency and/or rate at which nortriptyline metabolites are eliminated.
- Urinary pH: Modification of urinary pH to a level of “4” has been shown to increase excretion of nortriptyline metabolites by nearly 1000-fold. This indicates that if you take steps to actively acidify your urinary pH, the speed and amount of nortriptyline that is excreted via urine may significantly increase. Acidification of urinary pH can be accomplished via consuming more acidic foods and less alkaline ones. Be careful not to go overboard with this suggestion though as too much acidity may trigger acidosis. (Source: http://www.ncbi.nlm.nih.gov/pubmed/3015809)
- Exercise: When it comes to lipophilic drugs like nortriptyline, it is necessary to consider the possibility that with long-term administration and/or high-dose usage, metabolites may have accumulated within adipose tissues throughout the body. Accumulation of nortriptyline metabolites within adipose tissues may prolong its elimination. However, exercising to burn fat will reduce adipose tissue, possibly forcing nortriptyline out from the body at a quicker pace than usual.
How long has Nortriptyline stayed in your system after stopping?
If you’ve taken nortriptyline, share a comment regarding how long it took you to detoxify after your final dose. Do you think that nortriptyline was eliminated from your plasma at a fast, average, or slow pace? A fast elimination time would be considered under 4 days, an average elimination time is around 6 days, and a prolonged elimination term is anything over 1 week.
To help validate your speculation of how long nortriptyline remained in your system, mention interindividual factors that may have expedited or prolonged its clearance. Examples of such variables include your: CYP2D6 function, hepatic function, age, co-ingestion of CYP2D6 inhibitors/inducers, dosage, and term of administration. Realize that in most cases, nortriptyline will be out of your system and excreted within 1-2 weeks after your final dose.