Pharmaceutics of Anticancer Drugs Flashcards
What are the problems surrounding the pharmacokinetics of injected doxorubicin?
- 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)
What are the dangers of using Dox?
- Severe irritant; thrombophlebitis
- Extravasation = local necrosis, ulceration
Dox is a small potent cytotoxic, distributing through whole body rapidly after IV. How do we avoid systemic toxicity?
Combine cancer biology and pharmaceutics:
- Enhanced Permeation and Retention (EPR) effect
- Encapsulate Dox into virus-sized carrier
What is the EPR effect?
- 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
What is the path of a drug (Dox) in the circulation once injected?
- 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
What vehicle-related factors affect the EPR effect?
- Plasma residence time (more circulation = more time to aggregate)
- Particle size
- Carrier vehicle
- Polymer architecture
What tumour-related factors affect the EPR effect?
- Tumour type; large tumour exhibits EPR effect better than small
- Microenvironment
What external mediators affect the EPR effect?
- Radiation; disrupts tissue locally (can exploit EPR effect)
- Bradykinin antagonist
- COX inhibitor
- NO scavengers
Do all tumours exhibit EPR effect?
- Measured mostly in implanted tumours (limited data in metastases)
- Significant patient and tumour heterogeneity; not all tumours will show EPR effect
Why is prolonged circulation of the drug carrier important w/EPR targeting?
- Extravasation process at target tissue is slow and passive
What obstacles are there to long circulation of particulate/macromolecule carriers?
- Glomerular excretion by kidney (size matters)
- Recognition by RES (reticuloendothelial) system in the liver, spleen and lung (recognises viruses and bacteria)
How can glomerular excretion be avoided by drug delivery carriers?
- Using carriers with larger size than threshold value
- 42-50 kDa for water-soluble polymers
How can RES (reticuloendothelial) recognition be avoided by drug carriers?
- If drug carriers are < 200 nm
- Then will not activate complement cascade
How does the size, shape and charge of the drug carrier affect RES recognition?
- 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
What are the structural features of liposomal doxorubicin?
- 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
What is the function of the PEG corona/layer on liposomal doxorubicin?
- 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
What is the ideal size for liposomal doxorubicin, and why? What drawback is there?
- 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
How is higher loading of doxorubicin achieved into the liposome?
- 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
How does the half-life of liposomal dox compare with just the Dox HCl salt alone?
- Liposome; 55hrs
- HCl salt alone; 26hrs
> Longer circulation allows passive transport to tumour tissue with disrupted vasculature
Why is there drug leakage of liposomal dox during transport around the body?
Balance of stability of liposome and drug release (extravasation at tumour site)
Can accumulation occur at sites other than the tumour?
Yes, at sites with poor circulation e.g. fingers, toes other peripheries; can cause Palmar-plantar syndrome.
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?
- 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.
What are the problems of conventional formulation of paclitaxel, with polyoxyl castor oil and alcohol?
- Potent drug but almost insoluble in water
- Needs infusion over > 3 hrs via in-line filter (0.22 mm(
- Hypersensitivity common; surfactant
How can the issues of conventional paclitaxel formulation be solved w/biochemistry?
- Paclitaxel is almost insoluble
- But, can hijack albumin as carrier for paclitaxel; albumin in blood transports hydrophobic molecules (binding preferentially)
What is the proposed mode of action for a nab-paclitaxel complex (that hijacks albumin)?
- 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.
Tamoxifen is a weak base, with a pKa 8.8. What does this mean for solubility, and how is this remedied?
- Low aqueous solubility
- Converted to citrate salt to be given orally
What are the pharmacokinetics of tamoxifen driven by CYP-mediated metabolism?
- 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
Why are the active metabolites of Tamoxifen not administered instead, to combat CYP-profile dependency?
- Active metabolites have different solubility profiles
- Different abilities for active metabolites to be incorporated into formulation
