Evaluation of the changes in the gene CYP3A4 expression in HepG2 cells under ...
Gleevec group presentation#1
1. Imatinib
Gleevec®
Scott Denno, Michael Retz, Daniel Lasselle, Matt Wright, Emily Russell
http://www.pediatricgist.org/PediatricGIST/Treatment/Gleevec/tabid/6
9/Default.aspx
2. Gleevec® (Imatinib)
A tyrosine Kinase Inhibitor developed in the
late 1990's to treat Chronic Mylogenous
Leukemia which is a cancer of the lymphatic
system and bone. 1
CML is caused by a translocation of the 9th and
22nd chromosomes.1
Causes the Bcr-Abl oncogene to be created.1
Responsible for the activation of many signal
transduction pathways that cause the
characteristics of CML.
3. Mechanism of Action
Imatinib binds to Bcr/Abl protein very close
to the binding site of ATP, blocking ATP from
binding.2
Without the binding of ATP, Bcr/Abl
cannot phosphorylate substrate proteins.2
Imatinib is very specific to this sub-family of
receptor tyrosine kinases.2
4. (Figure 2. shows the binding of Bcr/Abl to ATP and then to Gleevec®.)
http://www.pitt.edu/~super1/lecture/lec45951/004.htm
5. Mechanism of Action
Blocking the ability of Bcr/Abl stops several
transduction pathways that cause the
excessive proliferation of partially
differentiated cells that lead to CML.4
The main oncogenes that are inhibited are
Ras, Myc, and STAT.4
Each of these oncogenes cause a signal cascade
that cause cell proliferation.4
6. (Figure 3. shows the transduction pathways implicated with Bcr/Abl activation.)
http://imaging.ubmmedica.com/cancernetwork/journals/oncology/2007
05/ONC05152007p00654f1.jpg
10. Absorption6
All doses of Imatinib should be taken with a meal and a large
glass of water
Doses of 400 mg or 600 mg should be administered once daily
Doses of 800 mg should be administered as 400 mg twice a day
Can be dissolved in water or apple juice for patients having
difficulty swallowing
11. Absorption6
Imatinib is well absorbed after oral
administration
Maximal drug concentration (Cmax) achieved
within 2 to 4 hours post dose.
Mean absolute bioavailability is 98%
Mean imatinib AUC increases proportionally with
increasing doses ranging from 25 to 1,000 mg
12. Absorption6
There is no significant change in the
pharmacokinetics of Imatinib upon repeated
dosing
Accumulation is 1.5-2.5-fold at steady state
when Imatinib is dosed once daily
At clinically relevant concentrations
Imatinib, binding to plasma proteins in in
vitro experiments is approximately
95%, mostly albumin and alpha-1 acid
glycoprotein
15. Metabolism
N-desmethyl-imatinib
(“CGP74588”)
N-
demethylatedpiperazine
derivative7
Main circulating
metabolite in humans7
MW = 479.587
Imatinib and N-
desmethyl-imatinib are
Chemical structure of the N- both mainly N-oxidized
demethylatedpiperazine derivate. in the liver8
de Kogel C E , Schellens J H M The Oncologist 2007;12:1390-1394
16. N-desmethyl-imatinib (“CGP74588”)
Active
Shows in vitro potency similar to parent drug7
Plasma AUC of metabolite ~15% that of parent drug7
Figure 5. Shows relative plasma AUC of Imatinib and GCP.
"ScienceDirect.com" ScienceDirect.com. N.p., n.d. Web. 12 Nov. 2012.
17. Other possible metabolites
http://www.hyphadiscovery.co.uk/production_of_mammalian_agrochemi
cal_microbial_metabolites.html
18. Excretion9
Urinary to Fecal Ratio is 1:5
Renal Excretion = 13% of dose
5% unchanged in urine
Fecal Excretion = 70% of the dose
20% unchanged in feces
Elimination Half-life about 18 hrs
Excretion generally the same in adults and
children
19. Excretion
Eliminated mainly as metabolites
(25% remained unchanged)9
Actively secreted in bile by several
drug transports from the ATP binding
cassette superfamily, mainly
ABCB1(P-glycoprotein) and ABCG2
(Bcrp)10
4 healthy volunteers11
25% dose recovered in 2 days
80% dose recovered in 7 days
http://www.phar.cam.ac.uk/research/vanveen/vanveenresearch.html
20. Excretion9
Though clearance
is variable based
on patient weight
and age, the
manufacturer does
not recommend
dose adjustment
Monitoring is
important to avoid
Figure 6. Imatinib plasma
toxicity concentration shown as
concentration(nmol/L) v. time(h).
http://dmd.aspetjournals.org/content/33/10/1503.full
21. References
1. Faderl S, Talpaz M, Estrov Z, O'Brian S, Kurzrock R, KantarjianH. The Biology of Chronic
Myeloid Leukemia. New England Journal of Medicine. 1999; 341: 164-172
2. DeVita V, Lawrence T, Rosenberg S, eds. DeVita, Hellman, and Rosenberg's Cancer: Principles
and Practice of Oncology. 9th ed. North American edition: Lippincott Williams &
Wilkins; 2011: 1962-1964
3. Druker BJ, Tamura S, Buchdunger E, et al. Effects of a selective inhibitor of the Abl tyrosine
kinase on the growth of Bcr-Abl positive cells. Nat Med. 1996;2:561-566.
4. Jabbour E, Cortes J, Kantarjian H. Optimal First-Line Treatment of Chronic Myeloid
Leukemia: How to Use Imatinib and What Role for Newer Drugs. Oncology. 2007; 21: 6
5. Brunton LL, Chabner BA, Knollman BC, eds. Pharmacological Basis of Therapeutics. 12th ed.
New York, NY: McGraw-Hill; 2011.
6. Peng B, Dutreix C, et al. AbosluteBioavailavbility of Imatinib(Gleevec®) Orally versus
Intravenous Infusion. Clinical Journal of Pharmacology. 2004; 44: 158-162
7. Product Information: GLEEVEC(R) oral tablet , imatinibmesylate oral tablet . Novartis Pharmaceutical
Corporation, East Hanover, NJ, 2005.
8. Truven Health Products. N.p., n.d. Web. 12 Nov. 2012.
9. Peng B, Lloyd P, Schran H. Clinical pharmacokinetics of imatinib. PubMed.gov.
2005;44(9):879-94.
10. Kogel CE, Schellens JHM, Imatinib. The Oncologist. 2007.
11. Gschwind, HP. Metabolism and disposition of imatinibmesylate in healthy volunteers. Drug
Metabolism and Disposition. 2005. July 6, 2005. doi:10.1124
Faderl S, Talpaz M, Estrov Z, O'Brian S, Kurzrock R, Kantarjian H. The Biology of Chronic Myeloid Leukemia. New England Journal of Medicine. 1999; 341: 164-17
DeVita V, Lawrence T, Rosenberg S, eds. DeVita, Hellman, and Rosenberg's Cancer: Principles and Practice of Oncology. 9th ed. North American edition: Lippincott Williams & Wilkins; 2011: 1962-1964Druker BJ, Tamura S, Buchdunger E, et al. Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nat Med. 1996;2:561-566.
First picture - Druker BJ, Tamura S, Buchdunger E, et al. Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nat Med. 1996;2:561-566.
Jabbour E, Cortes J, Kantarjian H. Optimal First-Line Treatment of Chronic Myeloid Leukemia: How to Use Imatinib and What Role for Newer Drugs. Oncology. 2007; 21: 6
Jabbour E, Cortes J, Kantarjian H. Optimal First-Line Treatment of Chronic Myeloid Leukemia: How to Use Imatinib and What Role for Newer Drugs. Oncology. 2007; 21: 6http://imaging.ubmmedica.com/cancernetwork/journals/oncology/200705/ONC05152007p00654f1.jpg
Brunton LL, Chabner BA, Knollman BC, eds. Pharmacological Basis of Therapeutics. 12th ed. New York, NY: McGraw-Hill; 2011.
Peng B, Lloyd P, Schran H. Clinical pharmacokinetics of imatinib. PubMed.gov. 2005;44(9):879-94. http://www.ncbi.nlm.nih.gov/pubmed/16122278. Accessed November 11, 2012.Kogel CE, Schellens JHM, Imatinib. The Oncologist. 2007. http://theoncologist.alphamedpress.org/content/12/12/1390.full Accessed November 18, 2012.Gschwind, HP. Metabolism and disposition of imatinibmesylate in healthy volunteers. Drug Metabolism and Disposition. 2005. July 6, 2005. doi:10.1124 http://dmd.aspetjournals.org/content/33/10/1503.full. Accessed November 10, 2012. Picture: Van Veen, H. Human Breast Cancer Resistance Protein. University of Cambridge http://www.phar.cam.ac.uk/research/vanveen/vanveenresearch.html.
Gschwind, HP. Metabolism and disposition of imatinibmesylate in healthy volunteers. Drug Metabolism and Disposition. 2005. July 6, 2005. doi:10.1124 http://dmd.aspetjournals.org/content/33/10/1503.full. Accessed November 10, 2012.