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Summary NWI-BM078 Molecular therapy
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Week 1 Pharmacodynamics and pharmacokineticsLE: Personalized healthcare
Advantages digital biomarkers for personalized healthcare
- Continuous monitoring versus 1 snapshot observation
- Real world data versus data from clinically controlled circumstances
- More comprehensive and rich data sets
- Truely personalized
Strong potential in molecular + clinical + digital + environmental biomarkers for optimal
insight in complex biological systems
- Better basis to drive Personalized health(care)
- Better support for phase 1, 2, 3, 4 clinical trials
LE: Pharmacology and drug disposition
Pharmacodynamics: what does the drug do to the patient.
Pharmacokinetics: what does the patient do to the drug.
Both fall under rational pharmacotherapy, which is mechanism-based pharmacotherapy.
Phases in pharmacology
Toxicokinetic phase=ADME
Agonist stimulates the receptor
Antagonist blocks the receptor
Competitive antagonist binds the same as agonist, but doesn’t activate → blocks agonist
Non-comp. antagonist covalent binding, so agonist is no competition
Drug-receptor interaction can take seconds to hours, depending on the receptors.
Covalent bindings are the strongest binders, so it is not going to lose the binding to the
receptor.
ADME = administration, distribution, elimination
Plasma is very important for absorption and distribution. It is a transport mechanism to get
compounds to different parts of the body and we can take samples of plasma
- Administration of compounds can go in different forms, for example: inhalation,
oral/rectal, intravenous, intramuscular.
- Elimination goes by urine, feces, milk/sweat and expired air for example.
First pass effect is in which a drug gets metabolized at a specific location in the body that
results in a reduced concentration of the active drug upon reaching its site of action or the
systemic circulation.
,Volume of distribution: Vd = (F * D)/ C0
F = bioavailability (mostly given as 100% after IV injection)
D = dose
C0 = amount in the blood
When there is more protein binding, more of the compound stays in the blood. The higher
the concentration, the more rapidly they go → elimination is an exponential process.
t1/2 = (Ln2 * V)/CL
t1/2 = halftime of a certain compound
Ln2 = because it’s an exponential process
V = volume of distribution
CL = clearance, so how long for the drug is removed from the body
Time between dosing is the dosing interval. If the time between dosing gets shorter, then
you see an accumulation. Not everything is removed before getting the new dose. Get into a
steady state.
Css = (F * D)/(delta t * CL)
Css = concentration at steady state
delta t = interval of drug dosing
Intravenous administration is directly injecting the drug into the blood, so no first pass effect.
Therapeutic index (TI) is the ratio between the dose of a drug that results in significant
toxicity and the dose that provides a therapeutic response. The smaller the space between
the effect and unwanted effect, the more difficult it is to get a drug on the market.
Zero-order kinetics describe reactions where the rate is not affected by the concentration of
the drug used. So there will be constant elimination regardless of the plasma concentration.
Genotoxic is the damage caused to the DNA by drugs. The glutathione conjugation by
GSTs can be a cellular protection mechanism to detoxify genotoxic molecules.
,LE: Transporters
ADME = absorption (intestine), metabolism (liver) and elimination (kidney)
ABC transporters
Are mainly causing efflux of drugs, so out of the cell. It is driven by ATP hydrolysis and is a
mediator in multidrug resistance (MDR1). Examples of roles of ABC transporters:
- Brain: maintaining BBB barrier
- Liver/kidney: detoxification
- Intestine: inhibitors could increase the bioavailability of many compounds
Common ABC-transporters are MDR1, P-glycoprotein (ABCB1). Have loops on the outside
and inside of the plasma membrane. When a drug binds to P-glycoprotein, the transporter
goes open and the drug is transported out. Examples of substrates are chemo/antibiotics.
MRP1 transports GSH and GSH conjugates out of the cell.
P-glycoprotein antagonists can be used to leave a cancer
drug in the cell to make it work. Done with Calcein efflux.
Drug transporters have overlapping substrate specificities
to be better safe than sorry, if one transporter doesn’t do
the function, it wants another to help.
Measuring transport activity: ATPase assay. The ATPase assay is an in vitro membrane
assay designed to indicate the nature of the interaction between the compound and the
transporter.
SLC transporters
Are mainly causing influx of drugs, so into the cell and often have multiple substrates.
Examples of SLC transporters are SLC22, OCTs, OCTNs and OATs.
LE: Biotransformation
Biotransformation is the metabolism of drugs, so to make it non toxic metabolites.
Metabolism is divided in three different phases, whereas phase III is the extraction
(transporters) phase.
Phase I: makes the compound more polar. Quite often induces an oxygen, also other
functional groups like OH, NH2, SH and COOH.
Oxidation is the most important phase I reaction of the cytochrome P450 (CYP450) system.
Most common subtype is CYP3A4 (50%). CYP inducers enhance the oxidative metabolism
of its substrates.
Phase II: in phase II our body wants to connect the hydrophilic products. The product is
made more soluble. It conjugates with substrate acetyl, methyl, glutathione sulfate and
glucuronide.
Glucuronidation involves the metabolism of parent compounds by
UDP-glucuronosyltransferases (UGTs) into hydrophilic and negatively charged glucuronides
that cannot exit the cell without the aid of efflux transporters.
, Week 2 Drug delivery and development
LE: Drug targeting and delivery part I
Mostly a nanomedicine contains a drug, a targeting ligand like an antibody, surface
modification and a matrix.
PLGA is a drug that is very frequently used. It’s biodegradable by hydrolysis and has a
hydrophobic matrix, so hydrophobic drugs can be inside.
The more barriers can be crossed the more comfortable the route of application (“pill versus
injection“). There are three types of capillary endothodelia:
- Continuous: skeletal muscle (lot of blood vessels).
- Fenestrated: diffusion of small
proteins from 60-80 nm. In
endocrine glands and glomeruli for
example.
- Sinusoid: cells can pass through by
incomplete basement membrane,
like lymph nodes and bone marrow,
30-40 um.
Transport across cellular barriers can be by
transcellular (endocytosis/transcytosis) and paracellular (across tight junctions).
Transport across the blood brain barrier, BBB, is hard to get in. Anything that will enter the
lumen will be pumped back by P-glycoprotein MDR. Can go on the transcytosis route, with
transferrin. Can conjugate a drug to transferrin so it gets recognized by the transferrin
receptor and there will be endocytosis.
→ Drug shouldn’t be a substrate for MDR proteins, because they will be transported out.
Drug delivery systems
Liposomes
Lipid bilayer: encapsulation of hydrophobic drugs
Lumen: encapsulation of hydrophilic drug
Acyl chains drive the geometry of liposomes. Fatty acids have one
hydrophilic head group and a tail and phospholipids have two head groups
and tails, making a lipid bilayer.
SUV/LUV/MVV = hydrophilic
MLV = hydrophobic
Benefit of MLV would be the rings of the bilayer, the more
lipid bilayers, the more hydrophobic groups can be brought
in.
SUV/LUV have more space for the drug, so good for higher
drug/matrix ratio.
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