medchem exam 2 ADMET 1

working on march 26th class, class 9, all done

drug pharmacodynamics descr

interaction w/ receptors, enzymes, lipids, DNA; the study of the biochemical, physiological, and molecular effects of drugs on the body; what a drug does to the body

pharmacokinetics descr

describes what the body does to a drug, analyzing its journey through ADME; how to get to targets, stability

toxicology descr very basic

safety

ADMET long

absorption, distribution, metabolism, excretion, toxicology

what is the Cmax?

highest concentration of a drug in the blood/CSF/target organ after a dose is given

this that affect how a drug is administered (3)

patient convenience, local action, drug properties

ways that drugs are administered (just list them) (2, 4)

oral: inhaler, pill
through skin: intravenous (into vein), intramuscular (into muscle), subcutaneous (layer of tissue beneath dermis/epidermis), transdermal (like a skin patch)

what type of administration is this? + descr

intravenous - concentration gets the full dose first and then decreases over time

oral administration descr

slower uptake- first a slower increase (lag time) then a slower decrease

therapeutic window descr

space between minimal effective [] and the place of adverse high effects

IV administration: label the orange (red (what is on the slide, not added by me) and blue)

red: biologically active (window of time when it is)
blue: minimal effective [] (MEC)

uptake, breakdown and elimination for drugs (what parts of ADMET are they)

uptake: absorption
breakdown: metabolism
elimination: excretion

half life def

time it takes to go to 50% of [drug] from max

label orange

half life (t_1/2)

half life egs for aspirine and ibuprofen

asprine: 0.38 hrs
ibuprogen: 2 hrs

area under curve def

total amount of the drug in circulation

what type of administration, what is the red bar, what is blue line

oral administration
red: pharmacological activity
blue: MEC

label left to right, oral administration

lag time, Cmax (relates to adverse drug reactions), Area under curve (from time 0 extrapolated to infinity)

label top to bottom (purple is the field that covers the ff orange)

purp: toxicology
orange: adverse side effects, therapeutic window

label left to right - what drug [] curves do diff routes of administration provide

intravenous, intramuscular, subcutaneous, oral

label left top then bottom, then right

drug half life, how (often)?
oral bioavailability, how much?

what does this image show?

in real life - often repeated oral dosing to get desired plasma [] (each color is a diff drug)

reasons for clinical failures of drugs in order of importance (3) (in 1988)

pharmacokinetics (most important!! 39% !), lack of efficacy, animal toxicity

what does the uptake of a drug depend on

rate of absorption - differs by indiv, what they ate, what transporters in gut, etc.

how how the percentage that ADMET affects successfulness of clinical trial changed 1988 to 2004

decreased significantly (from 39% to 8%)

first hurdle for oral dose

absorption, goes through the liver first

what is very important from pill to drug (4 points)

solubility in water!! determined by drugs ability to interact w/ water molecules
uncharged - H-bond donors (HBD), H bond acceptors (HBA)
charged - dipoles (H2O)
variability between chemicals is large

solubility of a drug what it means

>65 microgram/mL solubility not limiting absorption
<10 microgram/mL no absorption
hence candidate drug is often required to have solubility above 10 to facilitate preclinical testing

what is important for charged molecules to be soluble in water

ionization

what is important for charged molecules to be membrane permeable

having neutral species (non ionized)

absorption and molecular size (3)

large molecules need enough functional groups to be soluble, functional groups from hydrogen bonds w/ water molecules → solvation shell, to penetrate liquid membrane solvation shell needs to be disrupted

what does the MV have to be for it to be incompletely absorbed

MV > 500

Lipinski’s Rule of 5

one of the big dogmas for drug-like molecules
MW < 500, Log P < 5 (does compound prefer water of hydrophobic context, partition constant), H-bond donors < 5 (sum of OH and NHs), H bond acceptors < 10 (sum of N and O atoms w/ free pairs)

Log P descr

experimental measure of hydrophobicity

internal transport mechanisms after oral intake

from intestinal lumen, through gut epithelial cells with active transport; transporters really important!! diff transporters on each side cause polarized cells

4 diff types of transporters

amino acid transporter, oligopeptide, phosphate transporter, glucose transporter - we know specific examples for each

P-glycoprotein descr

“bad guy” - blocking it helps w/ absorption, uptake depends on how many you have; BUT involved in keeping foreign molecules out of the brain (BBB), also often upregulated in cancers

next hurdle after absorption

first pass effect - an orally administered drug is metabolized by the liver, intestines, or lungs, significantly reducing its active concentration before it reaches systemic circulation; impacts bioavailability

balance of drug uptake two ways

what else can happen w/ active transport and drug efflux

drug-drug interactions

label

absorption phase (first pass metabolism); elimination phase - metabolism excretion

first pass effect by the liver

metabolism by enzymes, like the cytochrome P450 family

paracetamol metabolism (2)

phase 1: CYP2E1, phase I reaction enzymes, after uptake by cell; phase 2: conjugation, using phase II reaction enzymes

what is drug metabolism

done by specialized enzymes, in order to make the drugs more water-soluble and ready to excrete via the kidneys, liver is the main site of metabolism for most drugs (also a bit in the GI, lungs)

metabolic stability def

determines the half life of a drug, important! Involves the inactivation of an active drug, activation of inactive drug (prodrug), increased excretion of more polar compounds

microbiome role

matters with ADMET quite a bit!!

metabolism/biotransformation descr (3 steps + what in between, egs)

lipophillic drug -(phase I- reactions, eg oxidation, reduction, hydrolysis; by CYP)→ functionalized drug (drug-XH, metabolite (has a OH group)) -(phase II rxns, eg glucoronidation, sulphation; conjugation (?)) → conjugated drug (makes it so that it is very water soluble and can be excreted by the kidneys)

eg of a phase I enzyme

Cytochrome P450

eg of phase II enzyme

UDP

CYP expl

haem enzyme - has a haem group which has an iron molecule in between; the iron molecule can activate oxygen which can oxidize what is inside it if it fits

what is drug binding to CYPs like?

drugs binding to their targets - about molecular interactions and making the right fit

what can N-containing groups act as for CYP?

CYP inhibitors

major isoforms for drug metabolism

2C9, 2D6, 3A4 - some people lack them and then some drugs dont work on them

variation in metabolism

diff people have diff CYP, depends on diet, genes, etc. can change over time too - why people react differently to different drugs

next part of drugs life

excretion - kidney goes into urine, liver and GI goes to faeces and bile

kidney basic numbers

180L/day filtered, excreted 2L/day

importance of plasma protein binding

blasma is 55-60% of blood volume, contains proteins that can bind drugs, eg albumin can bind weak acidic drugs, alpha1-Acid glycoprotein can bind basic (cationic drugs)

drug-drug interactions eg

warfarine - anti-coagulant w/ v low therapeutic window, v strong albumin binding
sulphonamide abx - very strong albumin binding, competes w/ warfarine leading to bleeding by high levels of free warfarine

what does this show

how diff drug drug interactions can effect drug concentration in blood

grapefruit juice and drugs

juice contains inhibitor for CYP3A4

side effects w/ drugs (3)

often via interaction with other proteins, depends on used drug [], could also be due to metabolites

phase I and phase II descr

drug can be metabolized directly by phase I OR metabolized by phase I then II