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Emerald Murrell PharmD Candidate /27/10

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Presentation on theme: "Emerald Murrell PharmD Candidate /27/10"— Presentation transcript:

1 Emerald Murrell PharmD Candidate 2011 8/27/10
CYP2B6 Polymorphisms Emerald Murrell PharmD Candidate 2011 8/27/10

2 About CYP2B6 Located on chromosome 19
Makes up about 2-10% of hepatic CYP content Also expressed in brain (significantly higher in smokers and alcoholics) Metabolizes 4% of the top 200 drugs Highly inducible (some substrates also autoinduce, and it is also inducible in stressed conditions, e.g. fasting) High interindividual variation

3 Substrates Artemisin Methadone Bupropion Nicotine Cyclophosmamide
Propofol Efavirenz Pethidine Ifosfamide Selegiline Ketamine Sertraline Meperidine Tamoxifen Diazepam Testosterone Mephenytoin Nevirapine Aflatoxin b1 MDMA (ecstasy) Sibutramine

4 Inhibitors and Inducers of 2B6
Clopidogrel- Potent inhibitor OC/HRT Efavirenz Paroxetine Fluoxetine Chlorpyrifos (insecticide) Fluvoxamine Sertraline Memantine Thiotepa Nelfinavir Ticlopidine- Potent inhibitor Clotrimazole & Itraconazole Raloxifene Inducers Lopinavir/Ritonavir Phenytoin Phenobarbital Rifampin Dexamethasone Carbamazepine Metamizole Efavirenz (autoinduces) Cyclophosphamide (auto) Artemisinin (autoinduces) Endosulfan

5 Definitions CYPs (or Cytochrome P450 genes) produce enzymes involved in synthesis and breakdown of molecules and are subdivided into groups and subfamilies (CYP3A4, CYP2C9, etc). Enzymes mostly found in liver, but also found throughout body (brain, intestine, etc). Different combinations of polymorphisms in these genes are haplotypes (CYP2B6*6, CYP2B6*1). Haplotype= a combination of alleles (DNA sequences) at different places (loci) on the chromosome that are transmitted together Non-synonymous= a SNP in which both wildtype and mutant forms lead to the same polypeptide sequence is termed synonymous (sometimes called a silent mutation) — if a different polypeptide sequence is produced they are nonsynonymous. SNP nomenclature:

6 Haplotypes with decreased activity in vivo
CYP2B6*6, CYP2B6*16, CYP2B6*26 Haplotype with increased activity in vivo CYP2B6*4

7 Where haplotypes are important in regard to therapy:
Efavirenz for HIV treatment Cyclophosphamide for chemotherapy Bupropion for smoking cessation Cardiac side effects and death from methadone

8 Effect on Efavirenz Therapy CYB2B6*6 haplotype
CYP2B6*6 has two nonsynonymous variants: CYP2B6:516G>T AND CYP2B6:785A>G With or without additional promoter variants: -1456T>G AND -750T>C or T>C Present in 15-40% Asian, >50% Black population, 26% Caucasian Successful Efavirenz dose reduction to 400mg or 200mg was done for CYP2B6*6/*6 and *6/*26 carriers whose EFV concentrations were extremely high (>6000 ng/ml).

9 Effect on Efavirenz Therapy 516G>T
The 516G>T SNP that is present in CYP2B6*6 is also present in *7, *9, and *13 Presence is associated with 3-fold decrease in CYP2B6 activity The TT genotype is associated with increased efavirenz exposure (resulting in CNS side effects). Also predicts increased risk of developing drug resistance among patients who discontinue efavirenz-containing regimens 983T>C Defining SNP of CYP2B6*18 allele, and found in linkage in the CYP2B6*16 haplotype Not observed in Asians, Caucasians. 4-9% Blacks, low frequency Hispanics Associated with increased efavirenz and nevirapine exposure

10 Effect on Bupropion Therapy CYP2B6*4
Presence of 785A>G SNP High frequency in ethnic groups (15% Asian, 50% Black) Clearance of bupropion increased 1.66-fold *1/*4 genotype had AUC of hydroxybupropion (active metabolite formed by 2B6) increased by 25% compared to *1/*1

11 Effect on Cyclophosphamide Therapy
CYP2B6*6 homozygotes have significantly higher clearance and shorter half-life of cyclophosphamide compared to CYP2B6*1 heterozygotes and homozygotes Specific SNPs in the promoter region or introns (-2320T>C, -750T>C, 15582C>T of intron 3, or 18492T>C) of CYP2B6 affected cyclophosphamide activation to 4-hydroxycyclophosphamide (AUC of 4-hydroxycyclophosphamide is significantly related to leukocytopenia and neutropenia). This knowledge can help predict adverse effects.

12 Effect on Doxorubicin and Cyclophosphamide Therapy
Higher dose delay (indicative of higher toxicity) was seen in CYP2B6*2 and CYP2B6*5 CYP2B6*2, CYP2B6*8, CYP2B6*9, CYP2B6*4 were associated with a worse outcome Bray J, Sludden J, Griffin MJ, Cole M, Verrill M, Jamieson D, Boddy AVInfluence of pharmacogenetics on response and toxicity in breast cancer patients treated with doxorubicin and cyclophosphamide. Br J Cancer 2010; 102(6):

13 Effect on Methadone Therapy
Methadone is a racemic mixture (R)-methadone: narcotic effect by activating µ-opiod receptor (S)-methadone: inhibits cardiac potassium channel CYP2B6 is selective for (S)-methadone metabolism Having decreased CYP2B6 activity increases plasma concentrations of (S)-methadone (but not (R)-methadone) and increase risk of cardiac side effects and death. *6/*6 genotype had increased risk of prolonged QTc

14 References Bray J, Sludden J, Griffin MJ, Cole M, Verrill M, Jamieson D, Boddy AVInfluence of pharmacogenetics on response and toxicity in breast cancer patients treated with doxorubicin and cyclophosphamide. Br J Cancer 2010; 102(6): Kirchheiner J, Klein C, Meineke I, et al. Bupropion and 4-OH-bupropion pharmacokinetics in relation to genetic polymorphisms in CYP2B6. Pharmacogenetics. 2003;13:619–26. T.E. Klein, J.T. Chang, M.K. Cho, K.L. Easton, R. Fergerson, M. Hewett, Z. Lin, Y. Liu, S. Liu, D.E. Oliver, D.L. Rubin, F. Shafa, J.M. Stuart and R.B. Altman, "Integrating Genotype and Phenotype Information: An Overview of the PharmGKB Project" (220k PDF), The Pharmacogenomics Journal 2001; 1: Thorn CF, Lamba JK, Lamba V, Klein, Teri E, Altman RB. PharmGKB summary: very important pharmacogene information for CYP2B6. Pharmacogenet Genomics 2010; 20(8): Wang H, Tompkins LM. CYP2B6: new insights into a historically overlooked cytochrome P450 isozyme. Curr Drug Metab. 2008;9:598–610. Wynn, Gary H, Jessica R Oesterheld, Kelly L Cozza, and Scott C Armstrong. Clinical Manual of Drug Interaction Principles for Medical Practice. Washington, DC: American Psychiatric Publishing, 2009.

15 References Eap CB, Crettol S, Rougier JS, Schlapfer J, Sintra Grilo L, Deglon JJ, Besson J, Croquette-Krokar M, Carrupt PA, Abriel H. Stereoselective block of hERG channel by (S)-methadone and QT interval prolongation in CYP2B6 slow metabolizers. Clin Pharmacol Ther. 2007;81(5):719–28. Ribaudo HJ, Haas DW, Tierney C, Kim RB, Wilkinson GR, Gulick RM, Clifford DB, Marzolini C, Fletcher CV, Tashima KT, Kuritzkes DR, Acosta EP. Pharmacogenetics of plasma efavirenz exposure after treatment discontinuation: an Adult AIDS Clinical Trials Group Study. Clin Infect Dis. 2006;42(3):401–7. Gatanaga H, Hayashida T, Tsuchiya K, Yoshino M, Kuwahara T, Tsukada H, Fujimoto K, Sato I, Ueda M, Horiba M, Hamaguchi M, Yamamoto M, Takata N, Kimura A, Koike T, Gejyo F, Matsushita S, Shirasaka T, Kimura S, Oka S. Clin Infect Dis. 2007;45(9):1230–7. Nakajima M, Komagata S, Fujiki Y, Kanada Y, Ebi H, Itoh K, Mukai H, Yokoi T, Minami H. Successful efavirenz dose reduction in HIV type 1-infected individuals with cytochrome P450 2B6 *6 and *26. Pharmacogenet Genomics. 2007;17(6):431–45.


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