CYP2B6 and Drug Interactions FDA Advisory Committee for Pharmaceutical Sciences Clinical Pharmacology Subcommittee November 18th, 2003. - PowerPoint PPT Presentation

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CYP2B6 and Drug Interactions FDA Advisory Committee for Pharmaceutical Sciences Clinical Pharmacology Subcommittee November 18th, 2003.

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Title: CYP2B6 and Drug Interactions FDA Advisory Committee for Pharmaceutical Sciences Clinical Pharmacology Subcommittee November 18th, 2003.


1
CYP2B6 and Drug InteractionsFDA Advisory
Committee for Pharmaceutical SciencesClinical
Pharmacology SubcommitteeNovember 18th, 2003.
  • Zeruesenay Desta PhD
  • David A Flockhart MD, PhD
  • Indiana University School of Medicine

2
Outline
  • CYP2B6 expression
  • CYP2B6 substrates
  • In vitro
  • In vivo?
  • CYP2B6 inhibitors
  • CYP inducers
  • Relevant in vivo data

3
CYP2B6 expression Late 1990s
  • Low level of protein expression
  • Minor component of the total hepatic CYPs (lt1 of
    total P450 in the liver)
  • Thought to play a relatively minor role in human
    drug metabolism

4
CYP2B6 Expression Initial Studies
Detection () Pmol/mg protein (range) References
13/13 (100)   Yamano et al 1989
12/12 (100)   Forrester et al., 1992
12/14 (86), Thai   Kirby et al 1993
12/50 (24) 1.4?1.5 (0-7) Mimura et al 1993
9/30 (30) (Japanese) ?0.25 (0-2) Shimada et al 1994
26/30 (87), Caucasian 1.0 (0-2.5) Shimada et al 1994
2/10 (20)   Baker et al 1995
?/40, Japanese 0.14?0.62 Guengerich et al 1995
?/32, Caucasian 1.4?1.8 Guengerich et al 1995
?/16 3 (0-17) Imaoka et al 1996
8/30 (27)   Boobis et al 1996
High level in Thai   Kim et al 1997
7/10 (70) 19.36?23.9) Tateishi et al 1997
2/10 (20) 2.65?5.94 Tateishi et al 1997
6/30 (20)   Edwards et al 1998
5
CYP2B6 Expression Recent Studies
Detection () Pmol/mg protein (range) Variability References
17/17 (100) 15?21 (0.5-70) 247-fold Code et al. 1997
24/26 (92) 10.9?9.5 (0-28)   Yang et al., 1998
19/19 (100) 9.77?17.6 (0.7-71.1) 107-fold Ekins et al 1998
28/28 (100) 24.9 ?18.2 (2-82) 41-fold Stresser et al, 1999
43/48 (90) 1.7 (0.4-8, n43 livers) 20 Gervot et al 1999
15/16 (94)   100-fold (n15) Faucette et al 2000
12/12 (100) 44.6 (1.5-148.4) 99-fold Hesse et al 2000
136/136 (100) 16.9?16.6 (0.5-95.5) 191-fold Lang et al. 2001

6
CYP2B6 Expression 2003
  • New mono- and polyclonal antibodies of higher
    sensitivity and specificity for CYP2B6 protein
    immuno-quantification
  • Greater frequency of detection (almost in all
    human livers tested)
  • Higher protein quantities
  • Average 6 of the total liver CYP450 content
  • Absolute maximum amounts up to 25 to 43.5

7
The CYP2B6 gene
  • CYP2B subfamily
  • CYP2B6 gene (functional)
  • CYP2B7 gene (nonfunctional)
  • CYP2B7-like pseudogene)
  • Mapped to chromosome 19 19q12 and 19q13.2
  • Contains 9 exons - encodes a protein with 491
    amino acids

8
CYP2B6 substrate drugs (in vitro)
  • HIV medications
  • Nevirapine
  • Efavirenz
  • DPC 963
  • Anticancer drugs
  • Cyclophosphamide
  • Ifosfamide
  • Tamoxifen
  • ThioTEPA
  • CNS acting drugs
  • S-mephobarbital
  • Propofol
  • Bupropion
  • Ketamine
  • Selegiline
  • Methadone
  • S-mephenytoin
  • Other drugs
  • RP 73401
  • Artemisinin
  • Benzphetamine
  • Cinnarizine
  • Diazepam
  • Clopidogrel
  • Lidocaine N-deethylation
  • Ticlopidine
  • Dextromethorphan
  • R-mianserin
  • Benzyloxyresorufin
  • Antipyrine
  • 4-Chloromethyl-7-ethoxycoumarin
  • 3-Cyano-7-ethoxycoumarin
  • 7-ethoxycoumarin
  • 7-Ethoxy-4-trifluoromethylcoumarin
  • Imipramine
  • methoxyflurane

9
CYP2B6 Xenobiotics
  • Styrene
  • 6-aminochrysene
  • Dibenzoa,hanthracene
  • Aflatoxin B
  • Nicotine
  • Methylenedioxymethamphetamine (ecstasy)
  • 2-dibromoethane
  • benzoapyrene
  • Phenanthrene
  • 6-aminochrysene
  • Methoxychlor
  • 1,3-butadiene
  • 2-chloro-1,1-difluoroethene
  • azinphos-methyl (AZIN)
  • chlorpyrifos (CPF)
  • diazinon (DIA)
  • parathion (PAR),
  • CYP2B6 endogenous substances
  • Testosterone
  • Estrone
  • 17beta-estadiol

10
Human metabolism of efavirenz (Ward et al., J
Pharmacol Exp Ther 2003)
11
CYP2B6 catalyses the metabolism of efavirienz
(1µM)
12
Effect of rifampin on efavirenz in healthy
volunteers
13
CYP2B6 Catalyses metabolism of an efavirenz
analog DPC 963
Drug Metab Dispos. 2003 Jan31(1)122-32.
14
CYP2B6 is a low affinity catalyst of
S-mephenytoin metabolism to Nirvanol
Km 564µM
  • Heyn et al Drug Metab Dispos 199624948-954

15
N-Demethylation of S-mephenytoin (200µM) by
CYP2C9 and CYP2B6
  • Ko, Desta and Flockhart. Drug Metab Dispos
    199826(8)775-778

16
Human Metabolism of Mephenytoin
17
R-mephenytoin as CYP2B6 substrate probe?
18
Inhibitors of CYP2B6
  • Inhibitors
  • Antidepressants (e.g. paroxetine and sertraline)
  • Antiretrovirals (e.g. nelfinavir and ritonavir)
  • Ticlopidine and clopidogrel
  • ThioTEPA

19
ThioTEPA is a specific cytochrome P450
inhibitor in vitro
IC50 ?5µM
20
Inhibition of CYP2B6 by thioTEPA
Ki4.8  0.3 µM (HLMs)
Ki6.2  0.7 µM (CYP2B6)
ThioTEPA therapeutic concentration 1.1-18.6 µM
21
Cyclophosphamide activation
22
Effect of thioTEPA on the PK of CPA
(Huitema et al. Cancer Chemother Pharmacol
200046119-127)
23
Inducers of CYP2B6
  • Rifampin
  • Hyperforin
  • Phenobarbital
  • Ritonavir
  • Phenytoin
  • Carbamazepine
  • HMG-CoA reductase inhibitors
  • Nevirapine
  • Efavirenz
  • Clotrimazole
  • Artemisinin

24
Conclusions
  • CYP2B6 is a significant contributor to hepatic
    CYP expression
  • The number of substrate drugs for CYP2B6 is
    growing rapidly
  • Efavirenz and buproprion are specific in vitro
    probes for CYP2B6 activity
  • ThioTEPA is a specific in vitro inhibitor of
    CYP2B6
  • No valuable, specific inhibitors of CYP2B6 in
    vivo have been demonstrated to date
  • Efavirenz is a potentially valuable in vivo probe
    for CYP2B6 activity

25
Effect of rifampin on efavirenz in healthy
volunteers
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