Morphine | DrugBank Online

Step 1

Pacifici GM: Metabolism and pharmacokinetics of morphine in neonates: A review. Clinics (Sao Paulo). 2016 Aug;71(8):474-80. doi: 10.6061/clinics/2016(08)11. [PubMed:27626479] Kim J, Ham S, Hong H, Moon C, Im HI: Brain Reward Circuits in Morphine Addiction. Mol Cells. 2016 Sep;39(9):645-53. doi: 10.14348/molcells.2016.0137. Epub 2016 Aug 9. [PubMed:27506251] Beltran-Campos V, Silva-Vera M, Garcia-Campos ML, Diaz-Cintra S: Effects of morphine on brain plasticity. Neurologia. 2015 Apr;30(3):176-80. doi: 10.1016/j.nrl.2014.08.004. Epub 2014 Nov 11. [PubMed:25444409] Klimas R, Mikus G: Morphine-6-glucuronide is responsible for the analgesic effect after morphine administration: a quantitative review of morphine, morphine-6-glucuronide, and morphine-3-glucuronide. Br J Anaesth. 2014 Dec;113(6):935-44. doi: 10.1093/bja/aeu186. Epub 2014 Jul 1. [PubMed:24985077] Lotsch J: Pharmacokinetic-pharmacodynamic modeling of opioids. J Pain Symptom Manage. 2005 May;29(5 Suppl):S90-103. doi: 10.1016/j.jpainsymman.2005.01.012. [PubMed:15907650] Hoskin PJ, Hanks GW: Morphine: pharmacokinetics and clinical practice. Br J Cancer. 1990 Nov;62(5):705-7. [PubMed:2245160] Glare PA, Walsh TD: Clinical pharmacokinetics of morphine. Ther Drug Monit. 1991 Jan;13(1):1-23. [PubMed:2057987] Stuart-Harris R, Joel SP, McDonald P, Currow D, Slevin ML: The pharmacokinetics of morphine and morphine glucuronide metabolites after subcutaneous bolus injection and subcutaneous infusion of morphine. Br J Clin Pharmacol. 2000 Mar;49(3):207-14. [PubMed:10718775] Shigeev S: Severity of opiate intoxication to gender and age. Soud Lek. 2007 Jan;52(1):21-4. [PubMed:17370507] FDA approvals [Link] NIH [Link] FDA Approved Drug Products: Infumorph Morphine Sulfate Injection [Link] FDA Approved Drug Products: Morphine Sulfate Oral Tablets [Link]

Step 2

Yamada H, Shimoyama N, Sora I, Uhl GR, Fukuda Y, Moriya H, Shimoyama M: Morphine can produce analgesia via spinal kappa opioid receptors in the absence of mu opioid receptors. Brain Res. 2006 Apr 14;1083(1):61-9. Epub 2006 Mar 10. [PubMed:16530171] Choi HS, Kim CS, Hwang CK, Song KY, Wang W, Qiu Y, Law PY, Wei LN, Loh HH: The opioid ligand binding of human mu-opioid receptor is modulated by novel splice variants of the receptor. Biochem Biophys Res Commun. 2006 May 19;343(4):1132-40. Epub 2006 Mar 23. [PubMed:16580639] Castro RR, Cunha FQ, Silva FS Jr, Rocha FA: A quantitative approach to measure joint pain in experimental osteoarthritis--evidence of a role for nitric oxide. Osteoarthritis Cartilage. 2006 Aug;14(8):769-76. Epub 2006 Mar 31. [PubMed:16580848] Johnson EA, Oldfield S, Braksator E, Gonzalez-Cuello A, Couch D, Hall KJ, Mundell SJ, Bailey CP, Kelly E, Henderson G: Agonist-selective mechanisms of mu-opioid receptor desensitization in human embryonic kidney 293 cells. Mol Pharmacol. 2006 Aug;70(2):676-85. Epub 2006 May 8. [PubMed:16682505] Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352] doi:10.1021/cn9000236 [Link]

Step 3

Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [PubMed:17139284] Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. [PubMed:17016423] Leventhal L, Silva RM, Rossi GC, Pasternak GW, Bodnar RJ: Morphine-6beta-glucuronide-induced hyperphagia: characterization of opioid action by selective antagonists and antisense mapping in rats. J Pharmacol Exp Ther. 1998 Nov;287(2):538-44. [PubMed:9808678] Kozak CA, Filie J, Adamson MC, Chen Y, Yu L: Murine chromosomal location of the mu and kappa opioid receptor genes. Genomics. 1994 Jun;21(3):659-61. [PubMed:7959748] Teodorov E, Modena CC, Sukikara MH, Felicio LF: Preliminary study of the effects of morphine treatment on opioid receptor gene expression in brain structures of the female rat. Neuroscience. 2006 Sep 1;141(3):1225-31. Epub 2006 Jun 6. [PubMed:16753266] doi:10.1021/cn9000236 [Link]

Step 4

Yamada H, Shimoyama N, Sora I, Uhl GR, Fukuda Y, Moriya H, Shimoyama M: Morphine can produce analgesia via spinal kappa opioid receptors in the absence of mu opioid receptors. Brain Res. 2006 Apr 14;1083(1):61-9. Epub 2006 Mar 10. [PubMed:16530171] Dortch-Carnes J, Russell KR: Morphine-induced reduction of intraocular pressure and pupil diameter: role of nitric oxide. Pharmacology. 2006;77(1):17-24. Epub 2006 Mar 13. [PubMed:16534251] Koch T, Wu DF, Yang LQ, Brandenburg LO, Hollt V: Role of phospholipase D2 in the agonist-induced and constitutive endocytosis of G-protein coupled receptors. J Neurochem. 2006 Apr;97(2):365-72. Epub 2006 Mar 15. [PubMed:16539674] Galeotti N, Stefano GB, Guarna M, Bianchi E, Ghelardini C: Signaling pathway of morphine induced acute thermal hyperalgesia in mice. Pain. 2006 Aug;123(3):294-305. Epub 2006 May 2. [PubMed:16650582] Asensio VJ, Miralles A, Garcia-Sevilla JA: Stimulation of mitogen-activated protein kinase kinases (MEK1/2) by mu-, delta- and kappa-opioid receptor agonists in the rat brain: regulation by chronic morphine and opioid withdrawal. Eur J Pharmacol. 2006 Jun 6;539(1-2):49-56. Epub 2006 Apr 6. [PubMed:16678156] Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352] Kieffer BL, Gaveriaux-Ruff C: Exploring the opioid system by gene knockout. Prog Neurobiol. 2002 Apr;66(5):285-306. [PubMed:12015197] doi:10.1021/cn9000236 [Link]

Step 5

Hutchinson MR, Lewis SS, Coats BD, Rezvani N, Zhang Y, Wieseler JL, Somogyi AA, Yin H, Maier SF, Rice KC, Watkins LR: Possible involvement of toll-like receptor 4/myeloid differentiation factor-2 activity of opioid inactive isomers causes spinal proinflammation and related behavioral consequences. Neuroscience. 2010 May 19;167(3):880-93. doi: 10.1016/j.neuroscience.2010.02.011. Epub 2010 Feb 21. [PubMed:20178837]

Step 6

Projean D, Morin PE, Tu TM, Ducharme J: Identification of CYP3A4 and CYP2C8 as the major cytochrome P450 s responsible for morphine N-demethylation in human liver microsomes. Xenobiotica. 2003 Aug;33(8):841-54. doi: 10.1080/0049825031000121608 . [PubMed:12936704] Daily EB, Aquilante CL: Cytochrome P450 2C8 pharmacogenetics: a review of clinical studies. Pharmacogenomics. 2009 Sep;10(9):1489-510. doi: 10.2217/pgs.09.82. [PubMed:19761371]

Step 7

Projean D, Morin PE, Tu TM, Ducharme J: Identification of CYP3A4 and CYP2C8 as the major cytochrome P450 s responsible for morphine N-demethylation in human liver microsomes. Xenobiotica. 2003 Aug;33(8):841-54. doi: 10.1080/0049825031000121608 . [PubMed:12936704] Takeda S, Ishii Y, Mackenzie PI, Nagata K, Yamazoe Y, Oguri K, Yamada H: Modulation of UDP-glucuronosyltransferase 2B7 function by cytochrome P450s in vitro: differential effects of CYP1A2, CYP2C9 and CYP3A4. Biol Pharm Bull. 2005 Oct;28(10):2026-7. [PubMed:16204972] Daily EB, Aquilante CL: Cytochrome P450 2C8 pharmacogenetics: a review of clinical studies. Pharmacogenomics. 2009 Sep;10(9):1489-510. doi: 10.2217/pgs.09.82. [PubMed:19761371]

Step 8

Coffman BL, Rios GR, King CD, Tephly TR: Human UGT2B7 catalyzes morphine glucuronidation. Drug Metab Dispos. 1997 Jan;25(1):1-4. [PubMed:9010622] Takeda S, Ishii Y, Iwanaga M, Mackenzie PI, Nagata K, Yamazoe Y, Oguri K, Yamada H: Modulation of UDP-glucuronosyltransferase function by cytochrome P450: evidence for the alteration of UGT2B7-catalyzed glucuronidation of morphine by CYP3A4. Mol Pharmacol. 2005 Mar;67(3):665-72. Epub 2004 Dec 20. [PubMed:15611481] Yamada H, Ishii K, Ishii Y, Ieiri I, Nishio S, Morioka T, Oguri K: Formation of highly analgesic morphine-6-glucuronide following physiologic concentration of morphine in human brain. J Toxicol Sci. 2003 Dec;28(5):395-401. [PubMed:14746343] Abildskov K, Weldy P, Garland M: Molecular cloning of the baboon UDP-glucuronosyltransferase 2B gene family and their activity in conjugating morphine. Drug Metab Dispos. 2010 Apr;38(4):545-53. doi: 10.1124/dmd.109.030635. Epub 2010 Jan 13. [PubMed:20071451]

Step 9

Ohno S, Kawana K, Nakajin S: Contribution of UDP-glucuronosyltransferase 1A1 and 1A8 to morphine-6-glucuronidation and its kinetic properties. Drug Metab Dispos. 2008 Apr;36(4):688-94. doi: 10.1124/dmd.107.019281. Epub 2008 Jan 10. [PubMed:18187562]

Step 10

Ohno S, Kawana K, Nakajin S: Contribution of UDP-glucuronosyltransferase 1A1 and 1A8 to morphine-6-glucuronidation and its kinetic properties. Drug Metab Dispos. 2008 Apr;36(4):688-94. doi: 10.1124/dmd.107.019281. Epub 2008 Jan 10. [PubMed:18187562]

Step 11

Abildskov K, Weldy P, Garland M: Molecular cloning of the baboon UDP-glucuronosyltransferase 2B gene family and their activity in conjugating morphine. Drug Metab Dispos. 2010 Apr;38(4):545-53. doi: 10.1124/dmd.109.030635. Epub 2010 Jan 13. [PubMed:20071451]

Step 12

Abildskov K, Weldy P, Garland M: Molecular cloning of the baboon UDP-glucuronosyltransferase 2B gene family and their activity in conjugating morphine. Drug Metab Dispos. 2010 Apr;38(4):545-53. doi: 10.1124/dmd.109.030635. Epub 2010 Jan 13. [PubMed:20071451]

Step 13

Green MD, King CD, Mojarrabi B, Mackenzie PI, Tephly TR: Glucuronidation of amines and other xenobiotics catalyzed by expressed human UDP-glucuronosyltransferase 1A3. Drug Metab Dispos. 1998 Jun;26(6):507-12. [PubMed:9616184]

Step 14

Zhou R, Perez-Aguilar JM, Meng Q, Saven JG, Liu R: Opioid binding sites in human serum albumin. Anesth Analg. 2012 Jan;114(1):122-8. doi: 10.1213/ANE.0b013e318232e922. Epub 2011 Oct 24. [PubMed:22025496]

Step 15

Schwab D, Fischer H, Tabatabaei A, Poli S, Huwyler J: Comparison of in vitro P-glycoprotein screening assays: recommendations for their use in drug discovery. J Med Chem. 2003 Apr 24;46(9):1716-25. [PubMed:12699389] Troutman MD, Thakker DR: Novel experimental parameters to quantify the modulation of absorptive and secretory transport of compounds by P-glycoprotein in cell culture models of intestinal epithelium. Pharm Res. 2003 Aug;20(8):1210-24. [PubMed:12948019] FDA Approved Drug Products: Morphine Sulfate Oral Tablets [Link]