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B33CAN - Pharmaceutics > Pharmaceutics of Anticancer Drugs > Flashcards

Pharmaceutics of Anticancer Drugs Flashcards

1
Q

What are the problems surrounding the pharmacokinetics of injected doxorubicin?

A
  • Dox rapidly cleared from blood post-injection
  • Distributed to tissues; lungs, liver, heart, spleen, kidneys
  • Rapid metabolism in liver to metabolites, including active metabolite doxorubicinol
  • 50% of a dose excreted in bile within 7 days; half is unchanged drug
  • Does not cross BBB, BUT may cross placenta.
  • Blood clearance triphasic, time to half life; 12 mins (initial HCl), 3.3 hours (protein binding), 30 hours
  • Cardiotoxicity is dose limiting; ROS and mitochondrial iron hypothesis (cardiomyocytes sensitive to damage)
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2
Q

What are the dangers of using Dox?

A
  • Severe irritant; thrombophlebitis

- Extravasation = local necrosis, ulceration

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3
Q

Dox is a small potent cytotoxic, distributing through whole body rapidly after IV. How do we avoid systemic toxicity?

A

Combine cancer biology and pharmaceutics:

  • Enhanced Permeation and Retention (EPR) effect
  • Encapsulate Dox into virus-sized carrier
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4
Q

What is the EPR effect?

A
  • Tumour tissue has disrupted endothelial wall/lining, due to angiogenesis (see Pharmacology; endothelial cells loosely connected w/inadequate pericyte coverage etc.)
  • Allows accumulation of nanoparticles/macromolecules/liposomes at tumour site
  • Distribution of drug to tumour regions with each circulation
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5
Q

What is the path of a drug (Dox) in the circulation once injected?

A
  • Drug injected into vein; passes to heart
  • Passes through pulmonary circulation
  • Heart then pumps it around tissues
  • Blood flow in tissues is slow; absorption is efficient
  • Drug returns to the heart through liver; metabolism beings
  • Round trip takes 10 to 30 seconds
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6
Q

What vehicle-related factors affect the EPR effect?

A
  • Plasma residence time (more circulation = more time to aggregate)
  • Particle size
  • Carrier vehicle
  • Polymer architecture
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7
Q

What tumour-related factors affect the EPR effect?

A
  • Tumour type; large tumour exhibits EPR effect better than small
  • Microenvironment
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8
Q

What external mediators affect the EPR effect?

A
  • Radiation; disrupts tissue locally (can exploit EPR effect)
  • Bradykinin antagonist
  • COX inhibitor
  • NO scavengers
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9
Q

Do all tumours exhibit EPR effect?

A
  • Measured mostly in implanted tumours (limited data in metastases)
  • Significant patient and tumour heterogeneity; not all tumours will show EPR effect
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10
Q

Why is prolonged circulation of the drug carrier important w/EPR targeting?

A
  • Extravasation process at target tissue is slow and passive
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11
Q

What obstacles are there to long circulation of particulate/macromolecule carriers?

A
  • Glomerular excretion by kidney (size matters)

- Recognition by RES (reticuloendothelial) system in the liver, spleen and lung (recognises viruses and bacteria)

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12
Q

How can glomerular excretion be avoided by drug delivery carriers?

A
  • Using carriers with larger size than threshold value

- 42-50 kDa for water-soluble polymers

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13
Q

How can RES (reticuloendothelial) recognition be avoided by drug carriers?

A
  • If drug carriers are < 200 nm

- Then will not activate complement cascade

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14
Q

How does the size, shape and charge of the drug carrier affect RES recognition?

A
  • Size; < 200nm (but not < 5nm; filtered out by kidneys)
  • Shape; sphere or rod preferable (not disc; looks like RBCs)
  • Charge; anionic and neutral preferable, cationic (positive) showed great uptake from liver
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15
Q

What are the structural features of liposomal doxorubicin?

A
  • Doxorubicin HCl is loaded into liposome by pH gradient; ‘trapped’ till membrane degradation
  • Liposomal phospholipid bilayer encapsulates drug
  • PEG poly(ethyleneglycol) corona/layer on the outside of the phospholipid bilayer
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16
Q

What is the function of the PEG corona/layer on liposomal doxorubicin?

A
  • Acts as ‘steric shield’
  • Neutral, v.soluble in water; layer of tightly bound water around liposome box
  • Thus protein trying to bind (e.g. albumin) would have to penetrate water ‘shield’, and then have to compress PEG chains to bind = massive energy penalty
17
Q

What is the ideal size for liposomal doxorubicin, and why? What drawback is there?

A
  • Diameter of 90-100nm; virus-sized, thus good at evading defences
  • However though good for transport in the body, 100nm presents a limiting factor for drug loading
18
Q

How is higher loading of doxorubicin achieved into the liposome?

A
  • Changing pH and counter-ion (HCl vs. NH4SO4) allows high loading of drug
  • Self-association of drug in liposome (precipitates in liposome)
  • Achieves high conc. of fibrous Dox gel in lipsome
19
Q

How does the half-life of liposomal dox compare with just the Dox HCl salt alone?

A
  • Liposome; 55hrs
  • HCl salt alone; 26hrs
    > Longer circulation allows passive transport to tumour tissue with disrupted vasculature
20
Q

Why is there drug leakage of liposomal dox during transport around the body?

A

Balance of stability of liposome and drug release (extravasation at tumour site)

21
Q

Can accumulation occur at sites other than the tumour?

A

Yes, at sites with poor circulation e.g. fingers, toes other peripheries; can cause Palmar-plantar syndrome.

22
Q

Small molecules diffuse in and out of tumours easily, but individual cancer cells within the tumour can pump out small molecules via efflux transporters. How does liposomal dox overcome this?

A
  • Liposomes also diffuse into ‘leaky’ tumour vasculature
  • Uptake of liposomes into individual cancer cells bypasses transporter proteins in cell membranes; passive endocytosis
  • No efflux pumps for liposomes
  • Release of Dox intracellularly avoids efflux pumps.
23
Q

What are the problems of conventional formulation of paclitaxel, with polyoxyl castor oil and alcohol?

A
  • Potent drug but almost insoluble in water
  • Needs infusion over > 3 hrs via in-line filter (0.22 mm(
  • Hypersensitivity common; surfactant
24
Q

How can the issues of conventional paclitaxel formulation be solved w/biochemistry?

A
  • Paclitaxel is almost insoluble
  • But, can hijack albumin as carrier for paclitaxel; albumin in blood transports hydrophobic molecules (binding preferentially)
25
Q

What is the proposed mode of action for a nab-paclitaxel complex (that hijacks albumin)?

A
  • Complex is 130nm in size
  • Dissolution in bloodstream
  • Single albumin can bind up to 6 or 7 molecules of pacitaxel
  • pacitaxel-albumin binds SPARC (Secreted Protein, Acidic and Rich in Cysteine) receptor, overexpressed in some tumours
  • Triggers gp60-mediated transcytosis across endothelial cells
  • Vesicles are then emptied into the subendothelial space and interstitium; tumor uptake and cell death.
26
Q

Tamoxifen is a weak base, with a pKa 8.8. What does this mean for solubility, and how is this remedied?

A
  • Low aqueous solubility

- Converted to citrate salt to be given orally

27
Q

What are the pharmacokinetics of tamoxifen driven by CYP-mediated metabolism?

A
  • Tamoxifen is a pro-drug; its active metabolite is 4-hydroxytamoxifen
  • Tamoxifen converted to active form by CYP3A4, CYP2C9, CYP2D6
  • Both bind to ER, but 4-hydroxytamoxifen (afimoxifene) and N-desmethyl-4-hydroxytamoxifen (endoxifen) have 30-100 times greater affinity with ER than tamoxifen itself
  • Peak plasma concentrations 4-7 hours after dose
28
Q

Why are the active metabolites of Tamoxifen not administered instead, to combat CYP-profile dependency?

A
  • Active metabolites have different solubility profiles

- Different abilities for active metabolites to be incorporated into formulation

B33CAN - Pharmaceutics (5 decks)

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