Loading Pathway...
Error: Pathway image not found.
Hide
Pathway Description
Propofol Metabolism
Homo sapiens
Category:
Metabolite Pathway
Sub-Category:
Metabolic
Created: 2022-02-02
Last Updated: 2023-10-25
Propofol is injected intravenously where 95-99% of the drug is bound to serum albumin and hemoglobin. 1-5% of it goes to the brain and skeletal muscles to preform its mechanism of action. The rest travels to the liver where it is transported a liver transporter like OCT1 into the liver. In the endoplasmic reticulum membrane of the liver, Propofol is metabolized by Cytochrome P450 2C9 or Cytochrome P450 2B6 to make the active metabolite 4-Hydroxypropofol. 4-Hydroxypropofol has a third of the hypnotic ability of Propofol. 4-Hydroxypropofol is further metabolized by UDP-glucuronosyltransferase 1-8, UDP-glucuronosyltransferase 1-9 to make the metabolite 1-Quinol glucuronide. 4-Hydroxypropofol can also be metabolized by an unknown enzyme to make the metabolite 4-Quinol sulfate. There is also a possibility that 4-Hydroxypropofol does not metabolize into further metabolites and remains as is. Propofol also metabolizes into the metabolite Propofol glucuronide with the enzyme UDP-glucuronosyltransferase 1-8 or the enzyme UDP-glucuronosyltransferase 1-9. This further is metabolized into the metabolite 1-Quinol glucuronide with an unknown enzyme. All of these metabolites are transported back into the blood via a liver transporter such as MRP3. Here they travel to the kidney where they undergo renal excretion. 4-Hydroypropofol as an active metabolite can have similar effects on the brain as propofol.
References
Propofol Metabolism References
Mazoit JX, Samii K: Binding of propofol to blood components: implications for pharmacokinetics and for pharmacodynamics. Br J Clin Pharmacol. 1999 Jan;47(1):35-42. doi: 10.1046/j.1365-2125.1999.00860.x.
Pubmed: 10073737
Zhou SF, Zhou ZW, Yang LP, Cai JP: Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675. Epub 2009 Sep 1.
Regev R, Katzir H, Yeheskely-Hayon D, Eytan GD: Modulation of P-glycoprotein-mediated multidrug resistance by acceleration of passive drug permeation across the plasma membrane. FEBS J. 2007 Dec;274(23):6204-14. doi: 10.1111/j.1742-4658.2007.06140.x. Epub 2007 Nov 6.
Mano Y, Usui T, Kamimura H: Substrate-dependent modulation of UDP-glucuronosyltransferase 1A1 (UGT1A1) by propofol in recombinant human UGT1A1 and human liver microsomes. Basic Clin Pharmacol Toxicol. 2007 Sep;101(3):211-4. [Article]
Mourao AL, de Abreu FG, Fiegenbaum M: Impact of the Cytochrome P450 2B6 (CYP2B6) Gene Polymorphism c.516G>T (rs3745274) on Propofol Dose Variability. Eur J Drug Metab Pharmacokinet. 2016 Oct;41(5):511-5.
Mikstacki A, Zakerska-Banaszak O, Skrzypczak-Zielinska M, Tamowicz B, Prendecki M, Dorszewska J, Molinska-Glura M, Waszak M, Slomski R: The effect of UGT1A9, CYP2B6 and CYP2C9 genes polymorphism on individual differences in propofol pharmacokinetics among Polish patients undergoing general anaesthesia. J Appl Genet. 2017 May;58(2):213-220.
Bright DP, Adham SD, Lemaire LC, Benavides R, Gruss M, Taylor GW, Smith EH, Franks NP: Identification of anesthetic binding sites on human serum albumin using a novel etomidate photolabel. J Biol Chem. 2007 Apr 20;282(16):12038-47. Epub 2007 Feb 20.
Sawas AH, Pentyala SN, Rebecchi MJ: Binding of volatile anesthetics to serum albumin: measurements of enthalpy and solvent contributions. Biochemistry. 2004 Oct 5;43(39):12675-85.
Lang T, Klein K, Fischer J, Nussler AK, Neuhaus P, Hofmann U, Eichelbaum M, Schwab M, Zanger UM: Extensive genetic polymorphism in the human CYP2B6 gene with impact on expression and function in human liver. Pharmacogenetics. 2001 Jul;11(5):399-415.
Pubmed: 11470993
Lang T, Klein K, Richter T, Zibat A, Kerb R, Eichelbaum M, Schwab M, Zanger UM: Multiple novel nonsynonymous CYP2B6 gene polymorphisms in Caucasians: demonstration of phenotypic null alleles. J Pharmacol Exp Ther. 2004 Oct;311(1):34-43. doi: 10.1124/jpet.104.068973. Epub 2004 Jun 9.
Pubmed: 15190123
Yamano S, Nhamburo PT, Aoyama T, Meyer UA, Inaba T, Kalow W, Gelboin HV, McBride OW, Gonzalez FJ: cDNA cloning and sequence and cDNA-directed expression of human P450 IIB1: identification of a normal and two variant cDNAs derived from the CYP2B locus on chromosome 19 and differential expression of the IIB mRNAs in human liver. Biochemistry. 1989 Sep 5;28(18):7340-8. doi: 10.1021/bi00444a029.
Pubmed: 2573390
Strassburg CP, Manns MP, Tukey RH: Expression of the UDP-glucuronosyltransferase 1A locus in human colon. Identification and characterization of the novel extrahepatic UGT1A8. J Biol Chem. 1998 Apr 10;273(15):8719-26. doi: 10.1074/jbc.273.15.8719.
Pubmed: 9535849
Huang YH, Galijatovic A, Nguyen N, Geske D, Beaton D, Green J, Green M, Peters WH, Tukey RH: Identification and functional characterization of UDP-glucuronosyltransferases UGT1A8*1, UGT1A8*2 and UGT1A8*3. Pharmacogenetics. 2002 Jun;12(4):287-97.
Pubmed: 12042666
Gong QH, Cho JW, Huang T, Potter C, Gholami N, Basu NK, Kubota S, Carvalho S, Pennington MW, Owens IS, Popescu NC: Thirteen UDPglucuronosyltransferase genes are encoded at the human UGT1 gene complex locus. Pharmacogenetics. 2001 Jun;11(4):357-68.
Pubmed: 11434514
Wooster R, Sutherland L, Ebner T, Clarke D, Da Cruz e Silva O, Burchell B: Cloning and stable expression of a new member of the human liver phenol/bilirubin: UDP-glucuronosyltransferase cDNA family. Biochem J. 1991 Sep 1;278 ( Pt 2):465-9. doi: 10.1042/bj2780465.
Pubmed: 1910331
Hillier LW, Graves TA, Fulton RS, Fulton LA, Pepin KH, Minx P, Wagner-McPherson C, Layman D, Wylie K, Sekhon M, Becker MC, Fewell GA, Delehaunty KD, Miner TL, Nash WE, Kremitzki C, Oddy L, Du H, Sun H, Bradshaw-Cordum H, Ali J, Carter J, Cordes M, Harris A, Isak A, van Brunt A, Nguyen C, Du F, Courtney L, Kalicki J, Ozersky P, Abbott S, Armstrong J, Belter EA, Caruso L, Cedroni M, Cotton M, Davidson T, Desai A, Elliott G, Erb T, Fronick C, Gaige T, Haakenson W, Haglund K, Holmes A, Harkins R, Kim K, Kruchowski SS, Strong CM, Grewal N, Goyea E, Hou S, Levy A, Martinka S, Mead K, McLellan MD, Meyer R, Randall-Maher J, Tomlinson C, Dauphin-Kohlberg S, Kozlowicz-Reilly A, Shah N, Swearengen-Shahid S, Snider J, Strong JT, Thompson J, Yoakum M, Leonard S, Pearman C, Trani L, Radionenko M, Waligorski JE, Wang C, Rock SM, Tin-Wollam AM, Maupin R, Latreille P, Wendl MC, Yang SP, Pohl C, Wallis JW, Spieth J, Bieri TA, Berkowicz N, Nelson JO, Osborne J, Ding L, Meyer R, Sabo A, Shotland Y, Sinha P, Wohldmann PE, Cook LL, Hickenbotham MT, Eldred J, Williams D, Jones TA, She X, Ciccarelli FD, Izaurralde E, Taylor J, Schmutz J, Myers RM, Cox DR, Huang X, McPherson JD, Mardis ER, Clifton SW, Warren WC, Chinwalla AT, Eddy SR, Marra MA, Ovcharenko I, Furey TS, Miller W, Eichler EE, Bork P, Suyama M, Torrents D, Waterston RH, Wilson RK: Generation and annotation of the DNA sequences of human chromosomes 2 and 4. Nature. 2005 Apr 7;434(7034):724-31. doi: 10.1038/nature03466.
Pubmed: 15815621
Hayer M, Bonisch H, Bruss M: Molecular cloning, functional characterization and genomic organization of four alternatively spliced isoforms of the human organic cation transporter 1 (hOCT1/SLC22A1). Ann Hum Genet. 1999 Nov;63(Pt 6):473-82. doi: 10.1017/S0003480099007770.
Pubmed: 11388889
Sakata T, Anzai N, Shin HJ, Noshiro R, Hirata T, Yokoyama H, Kanai Y, Endou H: Novel single nucleotide polymorphisms of organic cation transporter 1 (SLC22A1) affecting transport functions. Biochem Biophys Res Commun. 2004 Jan 16;313(3):789-93. doi: 10.1016/j.bbrc.2003.11.175.
Pubmed: 14697261
Itoda M, Saito Y, Maekawa K, Hichiya H, Komamura K, Kamakura S, Kitakaze M, Tomoike H, Ueno K, Ozawa S, Sawada J: Seven novel single nucleotide polymorphisms in the human SLC22A1 gene encoding organic cation transporter 1 (OCT1). Drug Metab Pharmacokinet. 2004 Aug;19(4):308-12.
Pubmed: 15499200
Highlighted elements will appear in red.
Highlight Compounds
Highlight Proteins
Enter relative concentration values (without units). Elements will be highlighted in a color gradient where red = lowest concentration and green = highest concentration. For the best results, view the pathway in Black and White.
Visualize Compound Data
Visualize Protein Data
Downloads
Settings