Codeine metabolic pathways

The metabolism of morphine and related opiates has been investigated extensively and reviewed/424 426 It tends to be very rapid after parenteral administration but unpredictable after oral dosage. Scheme 2.26 illustrates the major metabolic pathways for morphine (1), codeine (2), and heroin (256). 

Codeine activation to morphine by demeth-ylation is controlled by the activity of the polymorphic cytochrome CYP2D6 (181). The clinical relevance of this observation derives from thefactthat about 10%of Caucasians lackthis metabolic pathway. Because poor metaboliz-ers cannot activate this widely used drug, for... 

The metabolic pathways in plants and living organisms were studied by means of tritium-labeled morphine (508, 509). The use of unnaturally tritium-labeled codeine derivatives showed that P. somniferum is able to... 

Heroin is rapidly metabolized to the active and specific metabolite 6-MAM and further to morphine and conjugated morphine. In turn, morphine is quickly converted to its principal metabolite M3G and, more slowly and in smaller amounts, to M6G. In general, the metabolism pathway of opiates is complex, because the taking place of several reactions of interconversion makes it difficult to certainly evaluate what a patient has consumed. For example, it is hard to understand if the patient, who has been prescribed diamorphine or morphine sulphate, has also consumed illicit heroin. The diagnosis cannot be done on the basis of morphine and 6-MAM contents, because their presence can be due to prescribed medications. Acetyl codeine would be a very useful marker for illicit heroin consumption, but unfortunately has a short half-life of only 237 min. Also through the determination of codeine and norcodeine, it is possible to evaluate whether the patient has taken illicit heroin as a source of morphine, but the interpretation is still difficult if codeine has been used in addition to diamorphine or illicit heroin. 

Alkaloid biosynthetic pathways are under strict regulation in plants. Until now, our limited knowledge of the fundamental mechanisms involved in the control of alkaloid metabolism has severely restricted our ability to harness the vast biotechnological potential of these important secondary pathways. For example, the use of plant cell cultures for the commercial production of pharmaceutical alkaloids has not become a reality despite decades of empirical research. The application of traditional and modem biochemical, molecular, and cellular techniques has revealed important clues about the reasons why C. rosens cultures accumulate tabersonine and catharanthine, but not vindoline or vinblastine, and why opium poppy cultures produce sanguinarine, but not codeine or morphine. The inability of dedifferentiated cells to accumulate certain metabolites was interpreted as evidence that the operation of many alkaloid pathways is tightly coupled to the development of specific tissues. Recent studies have shown that alkaloid pathways are regulated at multiple levels,... 

Perpherazine and over-the-counter (OTC) ingredients codeine and dextromethorphan are made active by the debrisoquine-sparteine oxidative pathway. The percentage of an ethnic or racial population poorly metabolizing by this pathway varies greatly for example Switzerland 9-10%, Hungary 10%, United States 7%, Nigeria 3-8% and Japan 0.5% (Wood and Zhou, 1991), but if not will gain no pain relief. 

A combination of paracetamol (acetaminophen) plus codeine is especially well suited to post-peel pain, but should not be used in the hours following a phenol peel, as paracetamol (a phenol derivative) goes through the same detoxification pathways as phenol, which could create metabolic competition and the risks of toxicity associated with phenol might be increased. Preventive administration of benzodiazepines (lorazepam 2.5 mg before the peel and on the night of the peel before going to bed) relieves the anxiety caused by these unpleasant sensations and reduces the need for analgesics after the peel. In case of very severe, localized pain (extremely rare), a nerve block could be used. 

Despite the detection of COR and other known morphinan branch pathway enzymes in opium poppy cell cultures (63-65,67), morphine and codeine are not produced. The inability of cultured cells to accumulate morphine might reflect the absence of other relevant enzymes or structural proteins that preclude the formation of a requisite metabolic channel. Nevertheless, the efficient operation of the sang-uinarine pathway indicates that cultured opium poppy cells possess the essential regulatory, eellular, and metabolic components to support the biosynthesis and... 

Methylation is often a minor pathway of drug metabolism for some molecules, but enzymes are known which can convert normorphine to morphine [114—115], catechols to methoxycatechols [116] and normeperidine, nor-codeine, and norcornitine to their Af-methyl derivatives. The methyl donor for these Af-methyl transferases is 5-adeno.sylmethionine. 

Hydrocodone bitartrate is administered orally, with excellent absorption from the gastrointestinal tract and a bioavailability of approximately 50-60%. Peak serum concentrations of hydrocodone occur after approximately 1.3 hours, with an elimination half-life of approximately 3.8 hours, in normal adults. It is prohahly metabolized mostly in the liver and primarily cleared via renal pathways. Similar to codeine and oxycodone, hydrocodone is known to undergo metabolism by the cytochrome P450 isoenzyme CYP2D6, genetic polymorphisms of which may explain some of the observed interindividual variation noted with its use. This enzyme converts hydrocodone to hydrom or phone, which displays significantly more avid binding for p receptors and may account for much of hydrocodone s clinical effect. Concurrent use of hydrocodone with medications known to induce or inhibit this isoenzyme may thus alter its efficacy and toxicity. 

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