Metabolism hydromorphone

Codeine, hydrocodone, morphine, methadone, and oxycodone are substrates of the cytochrome P-450 isoenzyme CYP2D6.47 Inhibition of CYP2D6 results in decreased analgesia of codeine and hydrocodone due to decreased conversion to the active metabolites (e.g., morphine and hydromorphone, respectively) and increased effects of morphine, methadone, and oxycodone. Methadone is also a substrate of CYP3A4, and its metabolism is increased by phenytoin and decreased by cimetidine. CNS depressants may potentiate the sedative effects of opiates. 

Pharmacokinetic properties Hydrocodone is metabolized by CYP2D6 to the O-desmethyl derivative hydromorphone (Otton et al., 1993). Further steps of metabolization include N-demethylation and glucuronidation. 

Pharmacokinetic properties Hydromorphone (Hagen et al.,1995) is rapidly but incompletely absorbed from the gastrointestinal tract. It is metabolized in the gut and liver... 

Otton, S.V., Schadel, M., Cheung, S.W., Kaplan, H.L., Busto, U.E., Sellers, E.M. CYP2D6 phenotype determines the metabolic conversion of hydrocodone to hydromorphone, Clin. Pharmacol. Ther. 1993, 54, 463-472. 

Hydromorphone affects the respiratory center in the brain, and this is why it suppresses the cough reflex. Hydromorphone is partially broken down, or metabolized, by the liver and is absorbed by a variety of tissues and organs, including the gastrointestinal tract, smooth muscle, skeletal muscle, pancreas, lungs, cardiovascular system, and central nervous system. Once metabolized by the liver, hydromorphone moves out of the body by way of the kidneys and into the urine. The precise mechanisms by which hydromorphone and the other narcotic analgesics work are not entirely known. 

Hydrolysis in drug metabolism, 290 Hydromedin, 591 Hydromet, 663, 764 Hydromorphinol, xvii Hydromorphol, 665 Hydromorphone, 667 (metabolite), 665... 

Hydrocodone is a semisynthetic narcotic analgesic and a cough suppressant, similar to codeine. It is metabolized to the O- and IV-demethylated products, hydromorphone and norhydrocodone (1). 

Hydrocodone Metabolized to hydromorphone 3-4h Less nausea/constipation than codeine Similar to morphine... 

Studies have been conducted in animals to attempt to clarify the role of varying rates of drug metabolism in humans and animals and the likelihood for development of addiction/dependence to narcotics. Hydromorphone has been studied in several animal models because it is metabolized in humans by specific cytochrome P450 isoenzymes. So far, studies have looked at administration of agents that either block or promote P450 isoenzymes responsible for hydrocodone metabolism and the impact of enhanced or degraded metabolism of hydrocodone on those animal models. Results in rats and rhesus monkeys have demonstrated little effect from modifying hydrocodone metabolism. 

Figure 34-37 Hydrocodone and hydromorphone metabolic transformations.The figures in parenthesis are percent of a dose of hydrocodone excreted in urine. Rapid metabolizers excrete more hydromorphone conjugates (5.9%) compared with slow metabolizers (1.0%). Hydrocodo and hydromorphoi exist as 6-a and jl-stereiosomers. 6-a-hydrocodol is dihydrocodeine 6-a-hydromorphoi is dihydromorphine. For hydromorphone administration, 6% of the dose is excreted as the free parent drug and 30% as conjugates. Only trace amounts of hydromorphoi conjugates are formed.

Fig. 3. Modeled hydromorphone accumulation following repeated hydrocodone dosing as a function of CYP2D6 metabolizer status. Hydromorphone concentrations calculated are approximately five times higher in EMs compared with PMs following 10-mg hydrocodone dosing every 6 hours, based on genotype-specific peak hydromorphone serum concentrations [39]. EM, extensive metabolizer PM, poor metabolizer.

Cone EJ, Heit HA, Caplan YH, et al. Evidence of morphine metabolism to hydromorphone in pain patients chronically treated with morphine. J Anal Toxicol 2006 30 1-5. 

Biological synthesis of the analgesic hydromorphone, an intermediate in the metabolism of morphine, by Pseudomonas putidaMlO... 

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. 

Several of the opioids (buprenorphine, hydromorphone, methadone) are metabolised by CYP3A, at least in part, and their metabolism is expected to be reduced by the azoles, which, to varying extents, inhibit CYP3A4. This has been seen when fluconazole and voriconazole are given with methadone, and when ketocona-zole is given with buprenorphine. It has been suggested that keto-conazole inhibits the metabolism of morphine and oxycodone, but evidence for this is sparse. 

An isolated report describes a marked increase in the effects of dextromoramide, resulting in coma, in a man treated with trole-andomycin. Macrolides including troleandomycin and erythromycin are predicted to increase buprenorphine bioavailability. Similarly, the metabolism of hydromorphone is reduced by troleandomycin in vitro. Some manufacturers have su ested that the metabolism of methadone and oxycodone may be decreased by these macrolides, but there do not appear to be any clinical reports confirming this. 

An in vitro study suggested that quinidine did not significantly affect the metabolism of hydromorphone to norhydromorphone. Hydromorphone appears to be mainly metabolised by CYP3A, and to a lesser extent CYP2C9, but the inhibition of CYP2D6 by quinidine does not appear to affect norhydromorphone formation. ... 

Benetton SA, Borges VH Chang TKH, McErlane KM. Role of individual human cytochrome P450 enzymes in me in vitro metabolism of hydromorphone. Xenobiotica (2004) 34, 335-44. 

In a comparative study, 5 extensive metabolisers and 6 poor metabolisers of the cjTochrome P450 isoenzyme CYP2D6 were given hydroeodone, and another 4 extensive metabolisers of CYP2D6 were given hydrocodone after pre-treatment with quinidine. The metabolism of the hydroeodone to its active metabolite hydromorphone was found to be high in the extensive metabolisers who described good opiate effeets but poor in the poor metabolisers and the extensive metabolisers pre-treated with quinidine who described poor opiate effects . For the effeet of quinidine on hydromorphone metabolism, see Opioids -i- Quinidine , p.l83. 

Morphine is also hepatically metabolized to normorphine by the cytochrome P-450 enzymes GYP 3A4 and CYP2C8. Small amounts of codeine and hydromorphone are also produced, which is not clinically significant but can cause false positive urine drug tests for these substances. Morphine dosage should be reduced in patients with impaired renal function. 

As an oral drug, codeine is much less effective as an analgesic due to its large first-pass hepatic metabolism compared to morphine, hydrocodone and oxycodone. The plasma half-life of codeine is also shorter than many other orally available opiates such as morphine, hydromorphone, and oxymorphone. Like all opioids, continued use of codeine may result in tolerance development and physical dependence. However, when compared to potent mu agonists, codeine is less addictive and is associated with mild withdrawal symptoms. 

Continuous subcutaneous infusion is an alternative for patients who are unable to take hydromorphone orally. Patients with inadequate subcutaneous tissue, severe heart disease, renal, metabolic, electrolyte, fluid, or coagulation abnormalities should not be... 

This medication is absolutely contraindicated in patients who have a hypersensitivity or allergy to hydromorphone or other opioids. Hydromorphone is relatively contraindicated in those with acute or severe asthma or COED, conditions in which there is decreased ventilatory function, intracranial lesions or conditions associated with increased ICP, known or suspected paralytic ileus, or conditions resulting in respiratory depression or impairment. Patients with severe renal and/or hepatic impairment should be closely monitored for signs of respiratory depression as severe organ dysfunction may lead to poor drug metabolism and increase drug levels [3]. 

Hydrocodone has a half-life of 3.8 boms, peak effect at 1.3 hours, and a duration of 4.6 hours. It is metabolized by the liver and excreted primarily in urine. Hydrocodone is oxidized to hydromorphone by cytochrome P450 2D6. The extended-release formulation has measurably different pharmacokinetics following a single dose of 1,2 or 3 HC/ APAP CR tablet(s), the mean maximum plasma concentration (C ) ranged from 13.3 to 36.8 ng/mL for HC and 2.01 to 6.68 ng/mL for APAP. The mean time to reach (T ) was 6.0-6.7 hours for HC and 1.1-1.3 hours for APAP. Following twice-daily dosing of 2 HC/APAP CR tablets for 3 days, steady-state HC/APAP concentrations were attained by 24 hours [3,4]. The mean on day 3 was 37.0 ng/mL for HC and 4.96 ng/mL for APAP. Systemic exposures of HC and APAP demonstrated a dose-proportional increase from one to three tablets. Steady-state concentrations were reached by 24 hours with minimal accumulation following twice-daily administration. Thus, it can be taken every 12 hours [4]. 

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