Approximately 70 to 80% of the ingested dose of codeine is metabolized in the liver by conjugation with glucuronic acid to _codeine-6 glucuronide_ (C6G) and by O-demethylation to _morphine_ (about 5-10%) and N-demethylation to _norcodeine_ (about 10%) respectively. UDP-glucuronosyltransferase (UGT) 2B7 and 2B4 are the major metabolic enzymes mediating the glucurodination of codeine to the metabolite, _codeine 6 glucuronide_. Cytochrome P450 2D6 is the major enzyme responsible for the transformation of codeine to morphine and P450 3A4 is the main enzyme mediating the conversion of codeine to _norcodeine_. Morphine and norcodeine are then further metabolized by conjugation with glucuronic acid. The glucuronide metabolites of morphine are _morphine-3-glucuronide_ (M3G) and_ morphine-6-glucuronide _(M6G). Morphine and M6G have been proven to have analgesic activity in humans. The analgesic activity of C6G in humans is not known at this time. Norcodeine and M3G are generally not considered to have analgesic properties.
Codeine is metabolized in the liver by glucuronidation to codeine-6-glucuronide, by O-demethylation to morphine via CYP2D6, and by N-demethylation to norcodeine via CYP3A, all active metabolites. There is genetic polymorphism od CYP2D6. .. Poor /CYP2D6/ metabolizers have decreased analgesic effectiveness by inhibiting conversion of codeine to morphine. Concomitant administration with CYP2D6 inducers may result in increased metabolism and clearance of drug and also produce decreased clinical efficacy. Examples of CYP2D6 inducers include dexamethasone and rifampin.
... Results confirm biotransformation of codeine to ... normorphine in rodents.
来源:Hazardous Substances Data Bank (HSDB)
代谢
细胞色素P450 2D6（CYP2D6）是细胞色素P450（CYP）超家族的一员，参与临床毒理学中药物和滥用物质的生物转化。在CYP超家族中，CYP2D6基因被认为是最多态的，到目前为止已经识别出超过105种不同的等位基因。CYP2D6遗传多态性有潜力影响其底物的毒性。本综述将特别关注CYP2D6遗传多态性及其与人类因安非他命、阿片类止痛药和抗抑郁药中毒的相关性。PubMed（截至2013年8月）进行了以下选择标准的搜索：“CYP2D6 AND (毒理学 OR 中毒 OR 醉酒 OR 过量)”。在检索到的454篇引文中，只有46篇论文涉及CYP2D6多态性对安非他命、阿片类止痛药和抗抑郁药中毒的影响。
阿片类止痛药。CYP2D6超快速代谢者更有可能体验到可待因和曲马多的不良反应。因此，不依赖CYP2D6进行治疗活性的阿片类止痛药，如吗啡和氢吗啡酮，可能是可待因和曲马多的更好替代品，尽管这些药物有自己的不良反应。无论是CYP2D6代谢不良还是广泛/超快速代谢者，都可能暴露于安非他命、阿片类止痛药和抗抑郁药的毒性影响。在这三个类别中，证据水平取决于物质，同一药理类别内存在差异。
Cytochrome P450 2D6 (CYP2D6) is a member of the cytochrome P450 (CYP) superfamily involved in the biotransformation of drugs and substances of abuse encountered in clinical toxicology. Among the CYP superfamily, the CYP2D6 gene is considered as the most polymorphic as more than 105 different alleles have been identified so far. CYP2D6 genetic polymorphisms have the potential to affect the toxicity of their substrates. This review will focus specifically on CYP2D6 genetic polymorphisms and their relevance for poisoning due to amphetamines, opioid analgesics and antidepressants in humans. PubMed (up to August 2013) was searched with the following selection criteria: 'CYP2D6 AND (toxicology OR poisoning OR intoxication OR overdose)'. Of the 454 citations retrieved, only 46 papers dealt with the impact of CYP2D6 polymorphisms on poisoning due to amphetamines, opioid analgesics and antidepressants. ... Opioid analgesics. CYP2D6 ultra-rapid metabolizers are more likely to experience the adverse effects of codeine and tramadol. Opioid analgesics that do not rely on CYP2D6 for therapeutic activity, such as morphine and hydromorphone, may therefore be a better alternative to codeine and tramadol, with the limitation that these drugs have their own set of adverse reactions. ... Either poor or extensive/ultra-rapid CYP2D6 metabolizers may be exposed to toxic effects of amphetamines, opioid analgesics and antidepressants. In these three categories, the level of evidence is substance dependent, with differences within the same pharmacological class.
Opioid analgesics are commonly prescribed for acute and chronic pain, but are subject to abuse. Consequently, toxicology testing programs are frequently implemented for both forensic and clinical applications. Understanding opioid metabolism and disposition is essential for assessing risk of toxicity and, in some cases, providing additional information regarding risk of therapeutic failure. Opioids significantly metabolized by the cytochromeP450 (CYP450) enzyme system maybe subject to drug-drug interactions, including codeine, hydrocodone, oxycodone, fentanyl, meperidine, methadone, buprenorphine, and tramadol. CYP2D6 metabolism is polymorphic, and pharmacogenetic testing has been investigated for codeine, tramadol, oxycodone, and hydrocodone. CYP2B6 pharmacogenetic testing of methadone may reduce the risk of cardiac toxicity associated with the S-enantiomer. Opioids metabolized primarily by uridine 5'-diphospho-glucuronsyltransferase (UGT) enzymes include morphine, hydromorphone, dihydrocodeine, oxymorphone, levorphanol, and tapentadol. Parent and metabolite disposition is described for blood, oral fluid, and urine. Parent drug is most commonly detected in blood and oral fluid, whereas metabolites typically predominate in urine. Oral fluid/blood ratios exceed 1 for most opioids, making this an excellent alternative matrix for testing of this drug class. Metabolites of codeine, hydrocodone, and oxycodone are commercially available, and knowledge of metabolism is necessary for correct interpretation.
IDENTIFICATION AND USE: Codeine occurs as colorless or white crystals or powder. Codeine is an opiate, a component of opium, and an opioid agonist used as an analgesic, antitussive, and antidiarrheal agent. It commonly is given in combination with aspirin, acetaminophen, or other agents. It may also be used in veterinary care as an analgesic and antitussive. HUMAN EXPOSURE AND TOXICITY: Toxic doses of codeine may produce exhilaration, excitement, seizures, delirium, hypotension, miosis, slow pulse, tachycardia, narcosis, flushed facies, tinnitus, lassitude, muscular weakness, and circulatory collapse or respiratory paralysis. Cardiovascular side effects, ataxia, and headache have been observed in cases of accidental exposure. Respiratory arrest, coma, and death have occurred in young children receiving oral codeine doses of 5-12 mg/kg. Codeine should not be prescribed to children due to its poor analgesic effect and risk of opioid toxicity and oversedation. All opioid analgesics are metabolized by the liver and should be used with caution in patients with hepatic disease because increased bioavailability after oral administration of cumulative effects may occur. In patients with asthma or pulmonary emphysema, the indiscriminate use of antitussives may precipitate respiratory insufficiency. One case of opiate toxicity resulting in neonatal death has been reported in the nursing infant of a mother receiving codeine; genetic testing of the mother indicated that she was an ultrarapid metabolizer of codeine. First trimester use in 563 cases was associated with: respiratory malformations, genitourinary tract defects other than hypospadias, Down's syndrome, tumors, umbilical hernia, and inguinal hernia. After 2522 exposures to codeine anytime in pregnancy, the following were noted: hydrocephaly, pyloric stenosis, umbilical hernia, inguinal hernia. Chronic codeine-containing syrup abuse may be associated with disruptions in brain white matter (WM) integrity. These WM microstructural deficits may be linked to higher impulsivity in chronic codeine-containing syrup users. Codeine is metabolized in the liver by glucuronidation to codeine-6-glucuronide, by O-demethylation to morphine via CYP2D6, and by N-demethylation to norcodeine via CYP3A, all active metabolites. There is genetic polymorphism od CYP2D6. Poor CYP2D6 metabolizers have decreased analgesic effectiveness by inhibiting conversion of codeine to morphine. Concomitant administration with CYP2D6 inducers may result in increased metabolism and clearance of drug and also produce decreased clinical efficacy. Examples of CYP2D6 inducers include dexamethasone and rifampin. ANIMAL STUDIES: Codeine given intravenously to rabbits has in most instances reduced ocular pressure but occasionally has produced small rise. Hamsters and mice were gavaged with up to 300 or 150 mg/kg twice daily respectively. Decreased fetal weight was found at maternally toxic doses but no teratogenicity. Pregnant hamsters injected on day 8 subcutaneously with 73 to 360 mg/kg produced 6 to 8 percent cranioschisis in the offspring. In mice, codeine exposure during gestation failed to increase the incidence of major fetal malformations even at the highest dose (300 mg/kg, bid) which produced a significant increase in the percentage of resorptions per litter. The 300 mg/kg dose was also associated with a significant decrease in average fetal body weight per litter, and 19% mortality among pregnant females. Embryo/fetal development of the hamster was sensitive to codeine administered at a maternally nontoxic dose of 50 mg/kg, twice daily. At that dose, fetal body weight was significantly reduced while all parameters of maternal toxicity indicated no effect.There was no evidence of carcinogenic activity of codeine in male or female rats exposed to 400, 800, or 1,600 ppm of codeine for 2 years. There was no evidence of carcinogenic activity of codeine in male or female mice exposed to 750, 1,500, or 3,000 ppm of codeine for 2 years.
Opiate receptors are coupled with G-protein receptors and function as both positive and negative regulators of synaptic transmission via G-proteins that activate effector proteins. Binding of the opiate stimulates the exchange of GTP for GDP on the G-protein complex. As the effector system is adenylate cyclase and cAMP located at the inner surface of the plasma membrane, opioids decrease intracellular cAMP by inhibiting adenylate cyclase. Subsequently, the release of nociceptive neurotransmitters such as substance P, GABA, dopamine, acetylcholine and noradrenaline is inhibited. Opioids also inhibit the release of vasopressin, somatostatin, insulin and glucagon. Codeine's analgesic activity is, most likely, due to its conversion to morphine. Opioids close N-type voltage-operated calcium channels (OP2-receptor agonist) and open calcium-dependent inwardly rectifying potassium channels (OP3 and OP1 receptor agonist). This results in hyperpolarization and reduced neuronal excitability.
Despite wide use for many years, codeine has not been linked to serum enzyme elevations during therapy and there have been no convincing cases of idiosyncratic acute, clinically apparent liver injury attributed to its use.
Liklihood score: E (unlikely cause of clinically apparent liver injury).
References on the safety and potential hepatotoxicity of codeine are given in the Overview section of the Opioids.
Drug Class: Opioids
**Absorption** Codeine is absorbed from the gastrointestinal tract. The maximum plasma concentration occurs 60 minutes after administration. **Food Effects** When 60 mg codeine sulfate was given 30 minutes post-ingestion of a high high-calorie meal, there was no significant change in the absorption of codeine. **Steady-state concentration** The administration of 15 mg codeine sulfate every 4 hours for 5 days lead to steady-state concentrations of codeine, morphine, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) within 48 hours.
About 90% of the total dose of codeine is excreted by the kidneys. Approximately 10% of the drug excreted by the kidneys is unchanged codeine. The majority of the excretion products can be found in the urine within 6 hours of ingestion, and 40-60 % of the codeine is excreted free or conjugated, approximately 5 to 15 percent as free and conjugated morphine, and approximately 10-20% free and conjugated norcodeine.
来源:DrugBank
吸收、分配和排泄
分布容积
表观分布容积：约3-6 L/kg，表明药物在组织中广泛分布。
Apparent volume of distribution: about 3-6 L/kg, showing an extensive distribution of the drug into tissues.
Oral absorption of codeine is good, but there is a significant first-pass effect. The Vd is 2.6 L/kg, and there is a minimal protein binding. The onset os analgesic effect is 30 to 60 minutes, and antitussive effect is 1 to 2 hours. Peak effect is reached in 2 to 4 hours. ... Between 3% and 16% is excreted unchanged in the urine, and 90% of the absorbed dose if excreted via the kidney.
[EN] S-NITROSOMERCAPTO COMPOUNDS AND RELATED DERIVATIVES<br/>[FR] COMPOSÉS DE S-NITROSOMERCAPTO ET DÉRIVÉS APPARENTÉS
申请人：GALLEON PHARMACEUTICALS INC
公开号：WO2009151744A1
公开（公告）日：2009-12-17
The present invention is directed to mercapto-based and S- nitrosomercapto-based SNO compounds and their derivatives, and their use in treating a lack of normal breathing control, including the treatment of apnea and hypoventilation associated with sleep, obesity, certain medicines and other medical conditions.
[EN] DIHYDROPYRROLONAPHTYRIDINONE COMPOUNDS AS INHIBITORS OF JAK<br/>[FR] COMPOSÉS DE DIHYDROPYRROLONAPHTYRIDINONE COMME INHIBITEURS DE JAK
申请人：TAKEDA PHARMACEUTICAL
公开号：WO2010144486A1
公开（公告）日：2010-12-16
Disclosed are JAK inhibitors of formula (I) where G1, R1, R2, R3, R4, R5, R6, and R7 are defined in the specification. Also disclosed are pharmaceutical compositions, kits and articles of manufacture which contain the compounds, methods and materials for making the compounds, and methods of using the compounds to treat diseases, disorders, and conditions involving the immune system and inflammation, including rheumatoid arthritis, hematological malignancies, epithelial cancers (i.e., carcinomas), and other diseases, disorders or conditions associated with JAK.
[EN] ARYL ETHER-BASE KINASE INHIBITORS<br/>[FR] INHIBITEURS DE KINASES DE TYPE ARYLÉTHER-BASE
申请人：BRISTOL MYERS SQUIBB CO
公开号：WO2015038112A1
公开（公告）日：2015-03-19
The present disclosure is generally directed to compounds which can inhibit AAK1 (adaptor associated kinase 1), compositions comprising such compounds, and methods for inhibiting AAK1.
[EN] PYRAZOLO[1,5-a]PYRIMIDINE-BASED COMPOUNDS, COMPOSITIONS COMPRISING THEM, AND METHODS OF THEIR USE<br/>[FR] COMPOSÉS À BASE DE PYRAZOLO[1,5-A] PYRIMIDINE, COMPOSITIONS LES COMPRENANT ET UTILISATIONS DE CEUX-CI
申请人：LEXICON PHARMACEUTICALS INC
公开号：WO2013134228A1
公开（公告）日：2013-09-12
Pyrazolo[1,5-a]pyrimidine-based compounds of the formula: are disclosed, wherein R1, R2 and R3 are defined herein. Compositions comprising the compounds and methods of their use to treat, manage and/or prevent diseases and disorders mediated by mediated by adaptor associated kinase 1 activity are also disclosed.
[EN] METHYL OXAZOLE OREXIN RECEPTOR ANTAGONISTS<br/>[FR] MÉTHYLOXAZOLES ANTAGONISTES DU RÉCEPTEUR DE L'OREXINE
申请人：MERCK SHARP & DOHME
公开号：WO2016089721A1
公开（公告）日：2016-06-09
The present invention is directed to methyl oxazole compounds which are antagonists of orexin receptors. The present invention is also directed to uses of the compounds described herein in the potential treatment or prevention of neurological and psychiatric disorders and diseases in which orexin receptors are involved. The present invention is also directed to compositions comprising these compounds. The present invention is also directed to uses of these compositions in the potential prevention or treatment of such diseases in which orexin receptors are involved.
