Phenobarbital | DrugBank Online

Step 2

Kwan P, Brodie MJ: Phenobarbital for the treatment of epilepsy in the 21st century: a critical review. Epilepsia. 2004 Sep;45(9):1141-9. [PubMed:15329080] Taylor S, Tudur Smith C, Williamson PR, Marson AG: Phenobarbitone versus phenytoin monotherapy for partial onset seizures and generalized onset tonic-clonic seizures. Cochrane Database Syst Rev. 2001;(4):CD002217. [PubMed:11687150] Tudur Smith C, Marson AG, Williamson PR: Carbamazepine versus phenobarbitone monotherapy for epilepsy. Cochrane Database Syst Rev. 2003;(1):CD001904. [PubMed:12535420] Kalviainen R, Eriksson K, Parviainen I: Refractory generalised convulsive status epilepticus : a guide to treatment. CNS Drugs. 2005;19(9):759-68. [PubMed:16142991] Booth D, Evans DJ: Anticonvulsants for neonates with seizures. Cochrane Database Syst Rev. 2004 Oct 18;(4):CD004218. [PubMed:15495087] Pacifici GM: Clinical Pharmacology of Phenobarbital in Neonates: Effects, Metabolism and Pharmacokinetics. Curr Pediatr Rev. 2016;12(1):48-54. doi: 10.2174/1573397111666151026223914. [PubMed:26496779]

Step 3

Whiting PJ: The GABAA receptor gene family: new opportunities for drug development. Curr Opin Drug Discov Devel. 2003 Sep;6(5):648-57. [PubMed:14579514] Mehta AK, Ticku MK: An update on GABAA receptors. Brain Res Brain Res Rev. 1999 Apr;29(2-3):196-217. [PubMed:10209232] Yamakura T, Bertaccini E, Trudell JR, Harris RA: Anesthetics and ion channels: molecular models and sites of action. Annu Rev Pharmacol Toxicol. 2001;41:23-51. [PubMed:11264449] Krasowski MD, Harrison NL: General anaesthetic actions on ligand-gated ion channels. Cell Mol Life Sci. 1999 Aug 15;55(10):1278-303. [PubMed:10487207] Macdonald RL, McLean MJ: Anticonvulsant drugs: mechanisms of action. Adv Neurol. 1986;44:713-36. [PubMed:2871724] 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]

Step 4

Yamakura T, Bertaccini E, Trudell JR, Harris RA: Anesthetics and ion channels: molecular models and sites of action. Annu Rev Pharmacol Toxicol. 2001;41:23-51. [PubMed:11264449] Arias HR, Bhumireddy P: Anesthetics as chemical tools to study the structure and function of nicotinic acetylcholine receptors. Curr Protein Pept Sci. 2005 Oct;6(5):451-72. [PubMed:16248797] Krasowski MD, Harrison NL: General anaesthetic actions on ligand-gated ion channels. Cell Mol Life Sci. 1999 Aug 15;55(10):1278-303. [PubMed:10487207]

Step 5

Yamakura T, Bertaccini E, Trudell JR, Harris RA: Anesthetics and ion channels: molecular models and sites of action. Annu Rev Pharmacol Toxicol. 2001;41:23-51. [PubMed:11264449] Arias HR, Bhumireddy P: Anesthetics as chemical tools to study the structure and function of nicotinic acetylcholine receptors. Curr Protein Pept Sci. 2005 Oct;6(5):451-72. [PubMed:16248797] Krasowski MD, Harrison NL: General anaesthetic actions on ligand-gated ion channels. Cell Mol Life Sci. 1999 Aug 15;55(10):1278-303. [PubMed:10487207]

Step 6

Yamakura T, Bertaccini E, Trudell JR, Harris RA: Anesthetics and ion channels: molecular models and sites of action. Annu Rev Pharmacol Toxicol. 2001;41:23-51. [PubMed:11264449] Krasowski MD, Harrison NL: General anaesthetic actions on ligand-gated ion channels. Cell Mol Life Sci. 1999 Aug 15;55(10):1278-303. [PubMed:10487207] Jin LJ, Schlesinger F, Song YP, Dengler R, Krampfl K: The interaction of the neuroprotective compounds riluzole and phenobarbital with AMPA-type glutamate receptors: a patch-clamp study. Pharmacology. 2010;85(1):54-62. doi: 10.1159/000268641. Epub 2009 Dec 23. [PubMed:20051697]

Step 7

Yamakura T, Bertaccini E, Trudell JR, Harris RA: Anesthetics and ion channels: molecular models and sites of action. Annu Rev Pharmacol Toxicol. 2001;41:23-51. [PubMed:11264449] Krasowski MD, Harrison NL: General anaesthetic actions on ligand-gated ion channels. Cell Mol Life Sci. 1999 Aug 15;55(10):1278-303. [PubMed:10487207]

Step 8

Daniell LC: Effect of anesthetic and convulsant barbiturates on N-methyl-D-aspartate receptor-mediated calcium flux in brain membrane vesicles. Pharmacology. 1994 Nov;49(5):296-307. [PubMed:7862741]

Step 9

Faucette SR, Wang H, Hamilton GA, Jolley SL, Gilbert D, Lindley C, Yan B, Negishi M, LeCluyse EL: Regulation of CYP2B6 in primary human hepatocytes by prototypical inducers. Drug Metab Dispos. 2004 Mar;32(3):348-58. [PubMed:14977870] Kobayashi K, Yamagami S, Higuchi T, Hosokawa M, Chiba K: Key structural features of ligands for activation of human pregnane X receptor. Drug Metab Dispos. 2004 Apr;32(4):468-72. [PubMed:15039302]

Step 10

Madan A, Graham RA, Carroll KM, Mudra DR, Burton LA, Krueger LA, Downey AD, Czerwinski M, Forster J, Ribadeneira MD, Gan LS, LeCluyse EL, Zech K, Robertson P Jr, Koch P, Antonian L, Wagner G, Yu L, Parkinson A: Effects of prototypical microsomal enzyme inducers on cytochrome P450 expression in cultured human hepatocytes. Drug Metab Dispos. 2003 Apr;31(4):421-31. [PubMed:12642468] Mamiya K, Hadama A, Yukawa E, Ieiri I, Otsubo K, Ninomiya H, Tashiro N, Higuchi S: CYP2C19 polymorphism effect on phenobarbitone. Pharmacokinetics in Japanese patients with epilepsy: analysis by population pharmacokinetics. Eur J Clin Pharmacol. 2000 Feb-Mar;55(11-12):821-5. [PubMed:10805060] Yukawa E, Mamiya K: Effect of CYP2C19 genetic polymorphism on pharmacokinetics of phenytoin and phenobarbital in Japanese epileptic patients using Non-linear Mixed Effects Model approach. J Clin Pharm Ther. 2006 Jun;31(3):275-82. doi: 10.1111/j.1365-2710.2006.00712.x. [PubMed:16789993] 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. [PubMed:19515014] Pacifici GM: Clinical Pharmacology of Phenobarbital in Neonates: Effects, Metabolism and Pharmacokinetics. Curr Pediatr Rev. 2016;12(1):48-54. doi: 10.2174/1573397111666151026223914. [PubMed:26496779] Flockhart Table of Drug Interactions [Link]

Step 11

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. [PubMed:19515014] Kawalek JC, Howard KD, Farrell DE, Derr J, Cope CV, Jackson JD, Myers MJ: Effect of oral administration of low doses of pentobarbital on the induction of cytochrome P450 isoforms and cytochrome P450-mediated reactions in immature Beagles. Am J Vet Res. 2003 Sep;64(9):1167-75. [PubMed:13677397] Chen Y, Ferguson SS, Negishi M, Goldstein JA: Induction of human CYP2C9 by rifampicin, hyperforin, and phenobarbital is mediated by the pregnane X receptor. J Pharmacol Exp Ther. 2004 Feb;308(2):495-501. Epub 2003 Nov 4. [PubMed:14600250] Zhou D, Sunzel M, Ribadeneira MD, Smith MA, Desai D, Lin J, Grimm SW: A clinical study to assess CYP1A2 and CYP3A4 induction by AZD7325, a selective GABA(A) receptor modulator - an in vitro and in vivo comparison. Br J Clin Pharmacol. 2012 Jul;74(1):98-108. doi: 10.1111/j.1365-2125.2011.04155.x. [PubMed:22122233] Pacifici GM: Clinical Pharmacology of Phenobarbital in Neonates: Effects, Metabolism and Pharmacokinetics. Curr Pediatr Rev. 2016;12(1):48-54. doi: 10.2174/1573397111666151026223914. [PubMed:26496779] Phenobarbital Monograph [File]

Step 12

Lee AM, Joshi M, Yue J, Tyndale RF: Phenobarbital induces monkey brain CYP2E1 protein but not hepatic CYP2E1, in vitro or in vivo chlorzoxazone metabolism. Eur J Pharmacol. 2006 Dec 15;552(1-3):151-8. Epub 2006 Sep 16. [PubMed:17049344] Madan A, Graham RA, Carroll KM, Mudra DR, Burton LA, Krueger LA, Downey AD, Czerwinski M, Forster J, Ribadeneira MD, Gan LS, LeCluyse EL, Zech K, Robertson P Jr, Koch P, Antonian L, Wagner G, Yu L, Parkinson A: Effects of prototypical microsomal enzyme inducers on cytochrome P450 expression in cultured human hepatocytes. Drug Metab Dispos. 2003 Apr;31(4):421-31. [PubMed:12642468] Pacifici GM: Clinical Pharmacology of Phenobarbital in Neonates: Effects, Metabolism and Pharmacokinetics. Curr Pediatr Rev. 2016;12(1):48-54. doi: 10.2174/1573397111666151026223914. [PubMed:26496779]

Step 13

Gervot L, Rochat B, Gautier JC, Bohnenstengel F, Kroemer H, de Berardinis V, Martin H, Beaune P, de Waziers I: Human CYP2B6: expression, inducibility and catalytic activities. Pharmacogenetics. 1999 Jun;9(3):295-306. [PubMed:10471061] Faucette SR, Wang H, Hamilton GA, Jolley SL, Gilbert D, Lindley C, Yan B, Negishi M, LeCluyse EL: Regulation of CYP2B6 in primary human hepatocytes by prototypical inducers. Drug Metab Dispos. 2004 Mar;32(3):348-58. [PubMed:14977870] Wang H, Faucette SR, Gilbert D, Jolley SL, Sueyoshi T, Negishi M, LeCluyse EL: Glucocorticoid receptor enhancement of pregnane X receptor-mediated CYP2B6 regulation in primary human hepatocytes. Drug Metab Dispos. 2003 May;31(5):620-30. [PubMed:12695351] Madan A, Graham RA, Carroll KM, Mudra DR, Burton LA, Krueger LA, Downey AD, Czerwinski M, Forster J, Ribadeneira MD, Gan LS, LeCluyse EL, Zech K, Robertson P Jr, Koch P, Antonian L, Wagner G, Yu L, Parkinson A: Effects of prototypical microsomal enzyme inducers on cytochrome P450 expression in cultured human hepatocytes. Drug Metab Dispos. 2003 Apr;31(4):421-31. [PubMed:12642468] Flockhart Table of Drug Interactions [Link]

Step 14

Kawalek JC, Howard KD, Farrell DE, Derr J, Cope CV, Jackson JD, Myers MJ: Effect of oral administration of low doses of pentobarbital on the induction of cytochrome P450 isoforms and cytochrome P450-mediated reactions in immature Beagles. Am J Vet Res. 2003 Sep;64(9):1167-75. [PubMed:13677397] Gerbal-Chaloin S, Pascussi JM, Pichard-Garcia L, Daujat M, Waechter F, Fabre JM, Carrere N, Maurel P: Induction of CYP2C genes in human hepatocytes in primary culture. Drug Metab Dispos. 2001 Mar;29(3):242-51. [PubMed:11181490] Dvorak Z, Modriansky M, Pichard-Garcia L, Balaguer P, Vilarem MJ, Ulrichova J, Maurel P, Pascussi JM: Colchicine down-regulates cytochrome P450 2B6, 2C8, 2C9, and 3A4 in human hepatocytes by affecting their glucocorticoid receptor-mediated regulation. Mol Pharmacol. 2003 Jul;64(1):160-9. doi: 10.1124/mol.64.1.160. [PubMed:12815172] Klose TS, Blaisdell JA, Goldstein JA: Gene structure of CYP2C8 and extrahepatic distribution of the human CYP2Cs. J Biochem Mol Toxicol. 1999;13(6):289-95. doi: 10.1002/(sici)1099-0461(1999)13:6<289::aid-jbt1>3.0.co;2-n. [PubMed:10487415] Flockhart Table of Drug Interactions [Link]

Step 15

von Bahr C, Steiner E, Koike Y, Gabrielsson J: Time course of enzyme induction in humans: effect of pentobarbital on nortriptyline metabolism. Clin Pharmacol Ther. 1998 Jul;64(1):18-26. [PubMed:9695715] Venkatakrishnan K, von Moltke LL, Greenblatt DJ: Nortriptyline E-10-hydroxylation in vitro is mediated by human CYP2D6 (high affinity) and CYP3A4 (low affinity): implications for interactions with enzyme-inducing drugs. J Clin Pharmacol. 1999 Jun;39(6):567-77. [PubMed:10354960] Zhou SF, Xue CC, Yu XQ, Li C, Wang G: Clinically important drug interactions potentially involving mechanism-based inhibition of cytochrome P450 3A4 and the role of therapeutic drug monitoring. Ther Drug Monit. 2007 Dec;29(6):687-710. doi: 10.1097/FTD.0b013e31815c16f5. [PubMed:18043468] PHENOBARBITAL SODIUM INJECTION Prescribing Information - Sandoz Canada [Link]

Step 16

Sakuma T, Ohtake M, Katsurayama Y, Jarukamjorn K, Nemoto N: Induction of CYP1A2 by phenobarbital in the livers of aryl hydrocarbon-responsive and -nonresponsive mice. Drug Metab Dispos. 1999 Mar;27(3):379-84. [PubMed:10064569]

Step 17

Hukkanen J, Lassila A, Paivarinta K, Valanne S, Sarpo S, Hakkola J, Pelkonen O, Raunio H: Induction and regulation of xenobiotic-metabolizing cytochrome P450s in the human A549 lung adenocarcinoma cell line. Am J Respir Cell Mol Biol. 2000 Mar;22(3):360-6. [PubMed:10696073]

Step 18

Yoshinari K, Yoda N, Toriyabe T, Yamazoe Y: Constitutive androstane receptor transcriptionally activates human CYP1A1 and CYP1A2 genes through a common regulatory element in the 5'-flanking region. Biochem Pharmacol. 2010 Jan 15;79(2):261-9. doi: 10.1016/j.bcp.2009.08.008. Epub 2009 Aug 12. [PubMed:19682433] Sadar MD, Ash R, Sundqvist J, Olsson PE, Andersson TB: Phenobarbital induction of CYP1A1 gene expression in a primary culture of rainbow trout hepatocytes. J Biol Chem. 1996 Jul 26;271(30):17635-43. doi: 10.1074/jbc.271.30.17635. [PubMed:8663422] Sadar MD, Westlind A, Blomstrand F, Andersson TB: Induction of CYP1A1 by GABA receptor ligands. Biochem Biophys Res Commun. 1996 Dec 4;229(1):231-7. [PubMed:8954111]

Step 19

Gerbal-Chaloin S, Pascussi JM, Pichard-Garcia L, Daujat M, Waechter F, Fabre JM, Carrere N, Maurel P: Induction of CYP2C genes in human hepatocytes in primary culture. Drug Metab Dispos. 2001 Mar;29(3):242-51. [PubMed:11181490]

Step 20

Schuetz EG, Schuetz JD, Strom SC, Thompson MT, Fisher RA, Molowa DT, Li D, Guzelian PS: Regulation of human liver cytochromes P-450 in family 3A in primary and continuous culture of human hepatocytes. Hepatology. 1993 Nov;18(5):1254-62. [PubMed:8225233]

Step 21

Mastyugin V, Aversa E, Bonazzi A, Vafaes C, Mieyal P, Schwartzman ML: Hypoxia-induced production of 12-hydroxyeicosanoids in the corneal epithelium: involvement of a cytochrome P-4504B1 isoform. J Pharmacol Exp Ther. 1999 Jun;289(3):1611-9. [PubMed:10336559] McKinnon RA, Burgess WM, Gonzalez FJ, Gasser R, McManus ME: Species-specific expression of CYP4B1 in rabbit and human gastrointestinal tissues. Pharmacogenetics. 1994 Oct;4(5):260-70. [PubMed:7894498]

Step 22

Interactions [Link]

Step 23

Sakakibara Y, Katoh M, Kondo Y, Nadai M: Effects of Phenobarbital on Expression of UDP-Glucuronosyltransferase 1a6 and 1a7 in Rat Brain. Drug Metab Dispos. 2016 Mar;44(3):370-7. doi: 10.1124/dmd.115.067439. Epub 2015 Dec 18. [PubMed:26684499]

Step 24

Kawalek JC, Howard KD, Farrell DE, Derr J, Cope CV, Jackson JD, Myers MJ: Effect of oral administration of low doses of pentobarbital on the induction of cytochrome P450 isoforms and cytochrome P450-mediated reactions in immature Beagles. Am J Vet Res. 2003 Sep;64(9):1167-75. [PubMed:13677397] Madan A, Graham RA, Carroll KM, Mudra DR, Burton LA, Krueger LA, Downey AD, Czerwinski M, Forster J, Ribadeneira MD, Gan LS, LeCluyse EL, Zech K, Robertson P Jr, Koch P, Antonian L, Wagner G, Yu L, Parkinson A: Effects of prototypical microsomal enzyme inducers on cytochrome P450 expression in cultured human hepatocytes. Drug Metab Dispos. 2003 Apr;31(4):421-31. [PubMed:12642468] Al Koudsi N, Hoffmann EB, Assadzadeh A, Tyndale RF: Hepatic CYP2A6 levels and nicotine metabolism: impact of genetic, physiological, environmental, and epigenetic factors. Eur J Clin Pharmacol. 2010 Mar;66(3):239-51. doi: 10.1007/s00228-009-0762-0. Epub 2009 Dec 9. [PubMed:20012030] Donato MT, Viitala P, Rodriguez-Antona C, Lindfors A, Castell JV, Raunio H, Gomez-Lechon MJ, Pelkonen O: CYP2A5/CYP2A6 expression in mouse and human hepatocytes treated with various in vivo inducers. Drug Metab Dispos. 2000 Nov;28(11):1321-6. [PubMed:11038160]

Step 25

Schuetz EG, Beck WT, Schuetz JD: Modulators and substrates of P-glycoprotein and cytochrome P4503A coordinately up-regulate these proteins in human colon carcinoma cells. Mol Pharmacol. 1996 Feb;49(2):311-8. [PubMed:8632764] Luna-Tortos C, Fedrowitz M, Loscher W: Several major antiepileptic drugs are substrates for human P-glycoprotein. Neuropharmacology. 2008 Dec;55(8):1364-75. doi: 10.1016/j.neuropharm.2008.08.032. Epub 2008 Sep 11. [PubMed:18824002]

Step 26

Kiuchi Y, Suzuki H, Hirohashi T, Tyson CA, Sugiyama Y: cDNA cloning and inducible expression of human multidrug resistance associated protein 3 (MRP3). FEBS Lett. 1998 Aug 14;433(1-2):149-52. [PubMed:9738950] Cherrington NJ, Slitt AL, Maher JM, Zhang XX, Zhang J, Huang W, Wan YJ, Moore DD, Klaassen CD: Induction of multidrug resistance protein 3 (mrp3) in vivo is independent of constitutive androstane receptor. Drug Metab Dispos. 2003 Nov;31(11):1315-9. [PubMed:14570762] Slitt AL, Cherrington NJ, Maher JM, Klaassen CD: Induction of multidrug resistance protein 3 in rat liver is associated with altered vectorial excretion of acetaminophen metabolites. Drug Metab Dispos. 2003 Sep;31(9):1176-86. [PubMed:12920174] Ogawa K, Suzuki H, Hirohashi T, Ishikawa T, Meier PJ, Hirose K, Akizawa T, Yoshioka M, Sugiyama Y: Characterization of inducible nature of MRP3 in rat liver. Am J Physiol Gastrointest Liver Physiol. 2000 Mar;278(3):G438-46. [PubMed:10712264]

Step 27

Kast HR, Goodwin B, Tarr PT, Jones SA, Anisfeld AM, Stoltz CM, Tontonoz P, Kliewer S, Willson TM, Edwards PA: Regulation of multidrug resistance-associated protein 2 (ABCC2) by the nuclear receptors pregnane X receptor, farnesoid X-activated receptor, and constitutive androstane receptor. J Biol Chem. 2002 Jan 25;277(4):2908-15. Epub 2001 Nov 12. [PubMed:11706036]

Step 28

Kiuchi Y, Suzuki H, Hirohashi T, Tyson CA, Sugiyama Y: cDNA cloning and inducible expression of human multidrug resistance associated protein 3 (MRP3). FEBS Lett. 1998 Aug 14;433(1-2):149-52. [PubMed:9738950]

Step 29

Hagenbuch N, Reichel C, Stieger B, Cattori V, Fattinger KE, Landmann L, Meier PJ, Kullak-Ublick GA: Effect of phenobarbital on the expression of bile salt and organic anion transporters of rat liver. J Hepatol. 2001 Jun;34(6):881-7. [PubMed:11451172]

Step 30

Courtois A, Payen L, Le Ferrec E, Scheffer GL, Trinquart Y, Guillouzo A, Fardel O: Differential regulation of multidrug resistance-associated protein 2 (MRP2) and cytochromes P450 2B1/2 and 3A1/2 in phenobarbital-treated hepatocytes. Biochem Pharmacol. 2002 Jan 15;63(2):333-41. [PubMed:11841808] Schrenk D, Baus PR, Ermel N, Klein C, Vorderstemann B, Kauffmann HM: Up-regulation of transporters of the MRP family by drugs and toxins. Toxicol Lett. 2001 Mar 31;120(1-3):51-7. [PubMed:11323161] Kast HR, Goodwin B, Tarr PT, Jones SA, Anisfeld AM, Stoltz CM, Tontonoz P, Kliewer S, Willson TM, Edwards PA: Regulation of multidrug resistance-associated protein 2 (ABCC2) by the nuclear receptors pregnane X receptor, farnesoid X-activated receptor, and constitutive androstane receptor. J Biol Chem. 2002 Jan 25;277(4):2908-15. Epub 2001 Nov 12. [PubMed:11706036] Kauffmann HM, Schrenk D: Sequence analysis and functional characterization of the 5'-flanking region of the rat multidrug resistance protein 2 (mrp2) gene. Biochem Biophys Res Commun. 1998 Apr 17;245(2):325-31. [PubMed:9571149] Johnson DR, Habeebu SS, Klaassen CD: Increase in bile flow and biliary excretion of glutathione-derived sulfhydryls in rats by drug-metabolizing enzyme inducers is mediated by multidrug resistance protein 2. Toxicol Sci. 2002 Mar;66(1):16-26. [PubMed:11861969]