Hydrocodone metabolism

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. 

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. 

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. 

Hydrocodone has multiple actions, mainly involving the CNS and smooth muscle. Peak serum concentrations after single therapeutic doses are typically less than 30 ng/ml and occur within 1.5 h after drug administration.25 The plasma half-life has been reported to range from 3.4 to 8.8 h with a volume of distribution of 3.3 to 4.7 L/kg.25 In humans, hydrocodone is metabolized by O-demethylation (by the action of CYP2D6) and N-demethy 1 ation (by the action of CYP3A4) and... 

Initiate therapy of these drugs, particularly those with a narrow therapeutic index, at the lowest effective dose. Interaction is likely to be important with substrates for which CYP2D6 is considered the only metabolic pathway (e.g. hydrocodone, oxycodone, desipramine, paroxetine, chlorpheniramine, mesoridazine, alprenolol, amphetamines, atomoxetine)... 

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). 

Hutchinson MR, Menelaou A, Foster DJ, Coller JK, Somogyi AA. CYP2D6 and CYP3A4 involvement in the primary oxidative metabolism of hydrocodone by human liver microsomes. Br J Chn Pharmacol 2004 57(3) 287-97. 

Opioids cause a release of endorphins producing a feeling of pleasure. Examples of abuse include heroin, a highly addictive opioid that metabolizes to morphine and readily passes into the brain producing an immediate euphoria. Pharmaceutical or medicinal abused opioids include oxycontin, hydrocodone, codeine, methadone, and propoxyphene. 

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.

Lurcott G. The effects of the genetic absence and inhibition of CYP2D6 on the metabolism of codeine and its derivatives hydrocodone and oxycodone. Anesth Prog 1999 45 154-6. 

Susce MT, Murray-Carmichael E, de Leon J. Response to hydrocodone, codeine, and oxycodone in a CYP2D6 poor metabolizer. Prog Neuropsychopharmacol Biol Psychiatry 2006 30(7) 1356 8. 

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. 

Psychiatric A 60-year-old woman developed a psychosis after taking dextromethorphan at more than the recommended over-the-counter dosage, propoxyphene, and hydrocodone [71 ]. She developed religious and paranoid delusions, olfactory and visual hallucinations, and agitation. Propoxyphene may have slowed the metabolism of dextromethorphan, resulting in intoxication. 

Susceptibility factors Genetic A 5-year-old child died after being given hydrocodone bitartrate 1 mg/ml, 1 teaspoon tds [97" ]. Genetic analysis showed that the child had reduced ability to metabolize hydrocodone via CYP2D6. Co-administration of clarithromycin and valproic acid had further reduced drug elimination, leading to accumulation of lethal concentrations. 

There are approximately 100 CYP2D6 allelic variants identified however, there are basically four metabolizer states poor metabolizers (PM), who have two inactive genes and have no enzymatic activity intermediate metabolizers (IM), who have less than normal activity, usually one inactive and one low-activity gene extensive metabolizers (EM), who have one or two wild-type genes and ultrarapid metabolizers (UM), who possess more than two wild-type genes and increased enzymatic activity. These genetic variations may account for the differences in intrinsic clearance of 70-fold between EM and PM for codeine 0-demethylation, 10-fold for dihydrocodeine and oxycodone and 200-fold for hydrocodone. 

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