The principal pathways for the metabolism of codeine occur in the liver, although some metabolism occurs in the intestine and brain. Approximately 50-70% of codeine is converted to codeine-6-glucuronide by UGT2B7. Codeine-6-glucuronide has a similar affinity to codeine for the mu-opioid receptor, coded for by the OPRM1 gene. Approximately 10-15% of codeine is N-demethylated to norcodeine by CYP3A4. Norcodeine also has a similar affinity to codeine for the mu-opioid receptor. Between 0-15% of codeine is O-demethylated to morphine, the most active metabolite, which has a 200 fold greater affinity for the mu-opioid receptor compared to codeine. This metabolic reaction is performed by CYP2D6.
Approximately 60% of morphine is glucuronidated to morphine-3-glucuronide (M3G) while 5-10% is glucuronidated to morphine-6-glucuronide (M6G). These reactions are principally catalyzed by UGT2B7 in the liver. UGT1A1 may have a minor role in the formation of M3G, and UGT1A1 and UGT1A8 are capable of catalyzing the formation of M6G in vitro and so contribute to this pathway, although UGT1A8 is minimally expressed in the liver and so is not depicted here. M6G has a higher affinity for OPRM1 than morphine and M3G and so the ratio of morphine to M6G is considered an important indicator of analgesic effect.
Transporters are also depicted in this pathway, as they influence the clearance of codeine, morphine, and their metabolites. Some of the evidence for the involvement of these transporters was derived from experiments done in mice and may or may not be translatable to human pharmacokinetics. The transporters present at the blood-brain barrier, not depicted in this pathway, as well as metabolic enzymes and transporters in the brain and GI tract, likely also play an important role in the pharmacokinetics of codeine and morphine.
A disease linked to this pathway is Gilbert syndrome (visualised in pink), which is characterized by impaired glucuronidation due to a polymorphism in the gene encoding UGT1A1.b66a66cd3e96df0 N-demethylationa16O-dealkylationbfca16d03Conjugationb36abcbbdc58f03major enzyme involved Iinactive metabolite, a.k.a. M3Gmajor enzyme involved d03b2ab66N-demethylation, major proteind03 conjugationd03d03daca2fa8dd03d49e96f80d03debf90d03f1adbdb6bb74f58hepatocyteCL:0000182Cell Type18781855PubMedPharmacogenetic insights into codeine analgesia: implications to pediatric codeine use.Pharmacogenomics2008Madadi PKoren G10516633PubMedThe role of P-glycoprotein in blood-brain barrier transport of morphine: transcortical microdialysis studies in mdr1a (-/-) and mdr1a (+/+) mice.Br J Pharmacol1999Xie RHammarlund-Udenaes Mde Boer AGde Lange EC11186130PubMedGenetic polymorphism of UDP-glucuronosyltransferase 2B7 (UGT2B7) at amino acid 268: ethnic diversity of alleles and potential clinical significance.Pharmacogenetics2000Bhasker CRMcKinnon WStone ALo ACKubota TIshizaki TMiners JO16920476PubMedPharmacogenetics of morphine poisoning in a breastfed neonate of a codeine-prescribed mother.Lancet2006Koren GCairns JChitayat DGaedigk ALeeder SJ12185559PubMedMorphine glucuronide-to-morphine plasma ratios are unaffected by the UGT2B7 H268Y and UGT1A1*28 polymorphisms in cancer patients on chronic morphine therapy.Eur J Clin Pharmacol2002Holthe MKlepstad PZahlsen KBorchgrevink PCHagen LDale OKaasa SKrokan HESkorpen F12895198PubMedPharmacokinetics of morphine are not altered in subjects with Gilbert's syndrome.Br J Clin Pharmacol2003Skarke CSchmidt HGeisslinger GDarimont JLoetsch J8841154PubMedPharmacokinetics of morphine and its glucuronides after intravenous infusion of morphine and morphine-6-glucuronide in healthy volunteers.Clin Pharmacol Ther1996Loetsch JStockmann AKobal GBrune KWaibel RSchmidt NGeisslinger G12811366PubMedA pharmacogenetic study of uridine diphosphate-glucuronosyltransferase 2B7 in patients receiving morphine.Clin Pharmacol Ther2003Sawyer MBInnocenti FDas SCheng CRamirez JPantle-Fisher FHWright CBadner JPei DBoyett JMCook E JrRatain MJ1867957PubMedPharmacokinetics of codeine and its metabolites in Caucasian healthy volunteers: comparisons between extensive and poor hydroxylators of debrisoquine.Br J Clin Pharmacol1991Yue QYHasselstroem JSvensson JOSaewe Jcodeine and morphine drug pathwayPW:0001244Pathway Ontologyxenobiotics biodegradation pathwayPW:0000107Pathway Ontology17724700PubMedUGT2B7 promoter variant -840G>A contributes to the variability in hepatic clearance of morphine in patients with sickle cell disease.Am J Hematol2008Darbari DSvan Schaik RHCapparelli EVRana SMcCarter Rvan den Anker J15530129PubMedGenetic predictors of the clinical response to opioid analgesics: clinical utility and future perspectives.Clin Pharmacokinet2004Loetsch JSkarke CLiefhold JGeisslinger G16778732PubMedToxicokinetics of drugs of abuse: current knowledge of the isoenzymes involved in the human metabolism of tetrahydrocannabinol, cocaine, heroin, morphine, and codeine.Ther Drug Monit2006Maurer HHSauer CTheobald DS12492606PubMedPharmacokinetic modelling of morphine, morphine-3-glucuronide and morphine-6-glucuronide in plasma and cerebrospinal fluid of neurosurgical patients after short-term infusion of morphine.Br J Clin Pharmacol2002Meineke IFreudenthaler SHofmann USchaeffeler EMikus GSchwab MPrange HWGleiter CHBrockmoeller JGilbert syndromeDOID:2739Disease18719619PubMedPharmacogenetics of neonatal opioid toxicity following maternal use of codeine during breastfeeding: a case-control study.Clin Pharmacol Ther2009Madadi PRoss CJHayden MRCarleton BCGaedigk ALeeder JSKoren G15886284PubMedMice lacking multidrug resistance protein 3 show altered morphine pharmacokinetics and morphine-6-glucuronide antinociception.Proc Natl Acad Sci U S A2005Zelcer Nvan de Wetering KHillebrand MSarton EKuil AWielinga PRTephly TDahan ABeijnen JHBorst P2049245PubMedDisposition and metabolism of codeine after single and chronic doses in one poor and seven extensive metabolisers.Br J Clin Pharmacol1991Chen ZRSomogyi AAReynolds GBochner F8818573PubMedMicrosomal codeine N-demethylation: cosegregation with cytochrome P4503A4 activity.Drug Metab Dispos1996Caraco YTateishi TGuengerich FPWood AJ18622261PubMedSingle nucleotide polymorphism discovery and functional assessment of variation in the UDP-glucuronosyltransferase 2B7 gene.Pharmacogenet Genomics2008Innocenti FLiu WFackenthal DRamirez JChen PYe XWu XZhang WMirkov SDas SCook E JrRatain MJ12950465PubMedEvidence for an active transport of morphine-6-beta-d-glucuronide but not P-glycoprotein-mediated at the blood-brain barrier.J Neurochem2003Bourasset FCisternino STemsamani JScherrmann JM15625333PubMedCodeine intoxication associated with ultrarapid CYP2D6 metabolism.N Engl J Med2004Gasche YDaali YFathi MChiappe ACottini SDayer PDesmeules J18187562PubMedContribution of UDP-glucuronosyltransferase 1A1 and 1A8 to morphine-6-glucuronidation and its kinetic properties.Drug Metab Dispos2008Ohno SKawana KNakajin Sdrug pathwayPW:0000754Pathway Ontology1782973PubMedImpact of environmental and genetic factors on codeine analgesia.Eur J Clin Pharmacol1991Desmeules JGascon MPDayer PMagistris M8875123PubMedThe disposition of morphine and its 3- and 6-glucuronide metabolites in humans and animals, and the importance of the metabolites to the pharmacological effects of morphine.Drug Metab Rev1996Milne RWNation RLSomogyi AA12920168PubMedEvaluation of 3'-azido-3'-deoxythymidine, morphine, and codeine as probe substrates for UDP-glucuronosyltransferase 2B7 (UGT2B7) in human liver microsomes: specificity and influence of the UGT2B7*2 polymorphism.Drug Metab Dispos2003Court MHKrishnaswamy SHao QDuan SXPatten CJVon Moltke LLGreenblatt DJ9010622PubMedHuman UGT2B7 catalyzes morphine glucuronidation.Drug Metab Dispos1997Coffman BLRios GRKing CDTephly TR15051713PubMedA frameshift mutation and alternate splicing in human brain generate a functional form of the pseudogene cytochrome P4502D7 that demethylates codeine to morphine.J Biol Chem2004Pai HVKommaddi RPChinta SJMori TBoyd MRRavindranath V