drug pharmaceutical

1. Paclitaxel
Presented by:-
CHANDERHASH
Enrl No. – ASU2017010100041
4nd SEM
BSBT-522
Pharmaceutical Biotechnology
School of Bioscience

2. Content….
• Introduction
• Pharmacokinetics data of Paclitaxel
• How it was developed
• Market region
• Some Companies
• Real life problem
• How to Isolate paclitaxel
• How to Detect cancer cell
• Toxicity
• Pharmacological effects

3. Introduction
• Paclitaxel is used to treat various types of cancer. It is a cancer
chemotherapy drug that works by slowing or stopping cancer cell
growth.
• Paclitaxel has a possibility to interact with more drugs. These
interactions are harmful. Drug interactions can be prevented by
avoiding unwanted drug combinations.

4. Paclitaxel
Trade Name:- TAXOL
Molecular str.
Crystal Str.

5. Pharmacokinetic data
Bioavailability 6.5% (by mouth)
Protein binding 89 to 98%
Metabolism Liver (CYP2C8 and CYP3A4)
Elimination half-life 5.8 hours
Excretion Fecal and urinary

6. Paclitaxel is a mitotic inhibitor used in cancer
chemotherapy.
It was discovered in a US National Cancer
Institute program at the Research Triangle
Institute in 1967, E. Wall and Mansukh isolated
it from the bark of the Pacific yew tree, (Taxus
brevifolia) and named it taxol.
Later it was discovered that endophytic fungi in
the bark of synthesize paclitaxel.
How it was developed
The drug was finally selected for clinical trial
in 1977 by the Division of Cancer Treatment
(DCT).

7. This drug has been very complex to synthesize economically
from first principles and very complex to isolate from
natural sources.
Production of paclitaxel in large-scale bioreactors provides a
product with fewer contaminants, highly controllable and
reproducible.
Recent, commercial production of paclitaxel in stirred tank
vessel 30000.

8. Market region:-
• North America
• China
• Japan
• Southeast Asia
• India
Some Companies:-
• Phyton Biotech
• Scino Pharm
• Novasep
• South pharma

9. Real life problem
3 trees makes about 5 kg of bark
Need 120 kg of paclitaxel to treat 60,000 patients
8,000 kg of bark to make 120kg paclitaxel

10. TAXUS BREVIFOLIA
(STEM BARK)
METHANOL
CONCENTRATE
1.Extract with methanol
2.Evaporate
Step 1
Separation b/w CHLORINATED
SOLVENT and WATER
Step 2
CHLORINATED
SOLVENT LAYER
WATER LAYER
Step 3 1.Extract with Ethyl Acetate
Taxane Glycosides
concentrate
Step 4
1.Evaporate And Dissolve Residue in
Acetone
2. Precipitate Out Nonpolar impurities
with 50/50 Acetone /Hexane
3.Precipitation of Paclitaxel And Related
Taxanes with Hexane
1) ISOLATION

11. 4.Filtration
FILTRATE
(Impurities And Low
Polar Taxanes)
PRECIPITATE
(Paclitaxel And
Related Taxanes)
1.Drying
2.Flash Chromatography on silica
with Acetone/Chlorinated solvent
Step 5
Pre-Paclitaxel
Components
Paclitaxel Fraction Post –Paclitaxel
Fractions

12. Total 179 Clinical Trials (Data from NIH)
http://www.21cecpharm.com/px/clinic/
USES: -
• Lung cancer
Breast cancer

13. Clinically relevant concentrations of paclitaxel kill tumor cells by inducing multipolar divisions.
Cells entering mitosis in the presence of concentrations of paclitaxel equivalent to those in human breast
tumors form abnormal spindles that contain additional spindle poles.
Cells enter anaphase and divide their chromosomes in multiple directions.
PACLITAXEL CAUSE MULTIPOLAR DIVISIONS/ Detect cancer cell
M (Mitosis) Phase - Each replicated chromosome
comprises two chromatids.
(This is the Paclitaxel action point) Microtubules of
the cytoskeleton, responsible for cell shape, motility
and attachment, disassemble. And to grow the
mitotic spindle from the region of the centrioles.
Then Spindle fibers shorten, and the chromatids
(daughter chromosomes) are pulled apart and moving to
the cell poles. The cell devided into two daughter cells.

14. Two or three daughter cells are usually produced. Chromosome segregation is randomized due
to multipolar division followed by partial cytokinesis failure.
The resultant daughter cells are aneuploid, and a portion of these die (red X).

15. The Paclitaxel molecule shows a T-shaped or butterfly structure is
optimized within the beta-tubulin and exhibits functional
similarity to a portion of the B9-B10 loop in the alpha-tubulin.
This conformationoperating as a center of organization for a
diversity of secondarystructures. It permit intermolecular
hydrophobic associationas seen for the irregularly stacked C-3'
benzamido, His-229, and C-2 benzoyl moieties.
It brought the binding affinity, photoaffinity labeling, and
acquired mutation in human cancer cells.
Paclitaxel binding to Tubulins hetero-
dimer - a- Tubulin and b-Tubulin are
the basic units of Microtubule.This 3D
model shows the Paclitaxel molecule
binding Tubulin and make it stagged
together. The Microtubules cannot
disassemble, the cell cannot dividing.

17. Neutropenia and peripheral neuropathy are common clinical
side effects of paclitaxel
The most common dose-limiting toxicity of paclitaxel
neutropenia is typically of short duration and rarely associated
with other hematologic toxicities
Toxicity

18. 2) Pharmacological effects:-
 The taxane anticancer agents paclitaxel .
 Biologically and pharmacologically active compounds, and
their use as drug formulation vehicles has been implicated in
clinically important adverse effects, including acute
hypersensitivity reactions and peripheral neuropathy.
 Neuropathy, allergic reactions to cremaphor(preservative), Chest pain, Fluid
retention.
Common side effects : -
• Heart : Abnormal ECG, high blood pressure and increase heart beat rate.
• Central Nervous System : Nerve damage.
• Skin : Hair loss.
• Gastrointestinal : Nausea, vomiting, and diarrhea.
• Blood : Anemia, decrease in white blood cells, platelets and bleeding.
•Unusual bleeding (nose, mouth, vagina, or rectum), purple or red pinpoint spots under your skin.
• Liver : Elevated liver enzyme levels.
• Hypersensitivity : Severe allergic reactions such as rash, hives, trouble in breathing, etc.

19. Reference
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4161504/
https://www.drugbank.ca/drugs/DB01229
http://smpdb.ca/view/SMP00434?highlight[compounds][]=DB01229&highlight[proteins][]=DB01229
https://www.ncbi.nlm.nih.gov/pmc/articles/paclitaxel/naturalproductselect/products