Naltrexone metabolism

Kalyanaraman N. Inhibition of naltrexone metabolism by NSAIDs leading to metabolic switching and reactive metabolite formation. In MS. thesis. Minneapolis University of Minnesota, 2004. 

The therapeutic dose of acamprosate is 666 mg orally three times daily, and it is supplied as a 333 mg tablet. It can be started at the full dose in most patients without titration. It differs from disulfiram and naltrexone in that it is excreted by the kidneys without liver metabolism. Consequently, it is contraindicated in patients with severe renal impairment (creatinine clearance less than or equal to 30 mL/minute), and dose reduction is necessary when the creatinine clearance is between 30 and 50 mL/minute. The most common side effects are gastrointestinal and include nausea and diarrhea. Rates of suicidal thoughts were also increased in patients treated for 1 year with acamprosate (2.4%) versus placebo (0.8%). If necessary the total daily dose maybe decreased by 1 to 3 tablets (333-999 mg) per day to alleviate side effects. 

Morphine antagonists and partial agonists. The effects of opioids can be abolished by the antagonists naloxone or naltrexone (A), irrespective of the receptor type involved. Given by itself, neither has any effect in normal subjects however, in opioid-dependent subjects, both precipitate acute withdrawal signs. Because of its rapid presystemic elimination, naloxone is only suitable for parenteral use. Naltrexone is metabolically more stable and is given orally. Naloxone is effective as antidote in the treatment of opioid-induced respiratory paralysis. Since it is more rapidly eliminated than most opioids, repeated doses may be needed. Naltrexone may be used as an adjunct in withdrawal therapy. 

Absorption - Although well absorbed orally, naltrexone is subject to significant first-pass metabolism with oral bioavailability estimates ranging from 5% to 40%. Following oral administration, naltrexone undergoes rapid and nearly complete absorption with approximately 96% of the dose absorbed from the Gl tract. Peak plasma levels of naltrexone and 6- -naltrexol occur within 1 hour of dosing. 

Metabolism/Excretion-The major metabolite of naltrexone is 6- -naltrexol. 

Verebey, K., Volavka, J., Mule, S.J., and Resnick, R.B. (1976) Naltrexone disposition, metabolism, and effects after acute and chronic dosing. Clin Pharmacol Ther 20 315-328. 

An excellent brief article on buprenorphine treatment has been provided by Taikato et al. (2005), which notes the common possible side-effects (headaches, nausea and vomiting, sweating, constipation, etc.) and drug interactions. The limited central depressant effect of buprenorphine may be compounded by alcohol and antidepressants, while the metabolism of buprenorphine can be enhanced by anticonvulsants, with therefore possibly reduced efficacy. There have been some case reports of liver toxicity from buprenorphine that is reversible if the medication is stopped (Herve et al. 2004), and often clinical guidelines will recommend that liver function tests are included in buprenorphine treatment, as they definitely should be with naltrexone. 

Pharmacokinetic properties Naltrexone (Misra, 1981) is absorbed from the gastrointestinal tract, but is subject to considerable first-pass metabolism in the liver, yielding the active metabolite 6-beta-naltrexole. Naltrexone has low plasma binding of about 20%. The half-life of naltrexone is -3 h and of 6-beta-naltrexole is -13 h. 

Misra, A.L. Current status of preclinical research on disposition, pharmacokinetics, and metabolism of naltrexone, NIDA Res. Monogr. 1981, 28, 132-146. 

Wall, M.E., Brine, D.R., and Perez-Reyes, M., Metabolism and disposition of naltrexone in man after oral and intravenous administration, Drug Metab. Dispos., 9(4), 369-375, 1981. 

Nalorphine and naloxone are also more effective parenterally than orally. Both are first-pass metabolized in the liver very rapidly, largely by glucuronide formation/420 421 The effects of these antagonists are almost immediate upon intravenous administration and last between 1 and 4h. Naltrexone, on the other hand, maintains a good level of oral activity and has a half-life of around 10 h/422 423 ... 

Naltrexone (162), like naloxone, was more extensively metabolized after oral adminstration than following the parenteral route. Major metabolites in plasma, urine, and feces have been identified 459 by gc/ms as naltrexone-3-glucuronide and conjugated and unconjugated 6/3-hydroxy reduction product (270). The geometry at C-6 had been established during an earlier study. 460 Minor quantities of the C-2 oxidation product, 270, (R = OMe R = OH) and 270 (R = OMe, R = H) were also found. Oxycodone (44) gave the unusual 6/3,7/3-dihydroxy metabolite (271) in rabbits. 

Naloxone and naltrexone (pure antagonists) are not N-dealkylated in the brain although they are metabolized in this manner in the liver. 

Naloxone undergoes extensive hepatic first-pass metabolism through glucuronida-tion. Naltrexone is metabolized to the active metabolite 6-naltrexol, which is less potent but has a prolonged half-life compared to that of the parent drug. 

The disposition, metabolism and effects after acute and chronic dosing of naltrexone were investigated in 4 subjects, showing that narcotic antagonism was related to plasma levels of naltrexone.133... 

Release of Naltrexone. Naltrexone is a narcotic antagonist that occupies the same receptors as morphine but produces no euphoric effects. Therefore, a patient on naltrexone therapy experiences no euphoria upon intake of heroin which is rapidly metabolized in the body to morphine. Naltrexone therapy is currently a method of choice in the rehabilitation of opiate dependent individuals because it provides an enforced opiate free life [44]. 

Naltrexone, in a dose of 50 mg, will block the pharmacological effects of 25-mg heroin given intravenously for 24 hours, and the duration of blockade is dose-dependent. Naltrexone undergoes extensive first-pass metabolism, becoming converted to a 6-beta naltrexol, which is an active and pure narcotic-receptor antagonist and is excreted by the kidneys. Naltrexone can cause a dose-related hepatic injury. 

Various studies regarding the biotransformation of xenobiotic ketones have established that ketone reduction is an important metabolic pathway in mammalian tissue. Because carbonyl compounds are lipophilic and may be retained in tissues, their reduction to the hydrophilic alcohols and subsequent conjugation are critical to their elimination. Although ketone reductases may be closely related to the alcohol dehydrogenases, they have distinctly different properties and use NADPH as the cofactor. The metabolism of xenobiotic ketones to free alcohols or conjugated alcohols has been demonstrated for aromatic, aliphatic, alicyclic, and unsaturated ketones (e.g., naltrexone, naloxone, hydromorphone, and daunorubicin). The carbonyl reductases are distinguished by the stereospecificity of their alcohol metabolites. 

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