13203971
Description
Flashcards by Zena Dodds, updated more than 1 year ago
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Created by Zena Dodds
about 6 years ago
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| Question | Answer |
| what is metabolism and pharmokinetics | metabolism= how the body breaks down molecules Pharmokinetics = total process of drug disposition |
| What does ADME stand for? +2 bonus | Absorption, distribution, metabolism, elimination (excretion& dispostion) |
| defiintion of each ADME? PT1 ADM | Absorption:all processes from site of administration to the site of measurement Distruption: The reversible transfer of drug between the site of measurement and other sites within the body Metabolism: the loss of drug from the body by biochemical conversion |
| defintion of ADME? PT2 E +2bonus | Elimination: the loss of drug from the site of measurement within in the body Excretion: the irreversible loss of drug from the body Disposition: elimination +distrubtion |
| what is the main goal of DMPK | Reach the target site at a sufficient concentration, and remain for sufficient duration to elicit desired effect |
| Whats the difference between in VITRO and in VIVO | in vivo = inside living cells in vitro = tests/labs etc |
| what are 8 industry standard in vitro DMPK areas to assay | in silico tools measured physiochemical props chemical stability permeability metabolism cDDI and bioactivation risk Protein binding Pgp |
| what are the measured physiochemcal properties | pKa, LogP/D, Solubility, Aqueous kinetic |
| What is checked for in chemical stability assays | SGF, Buffer, Plasma/blood |
| what is checked for in permeability | PAMPA, intracellular drug connections |
| whats checked for in metabolism assays | metabolic stability, Cli in microsomes, hepatocytes, cytosol - Reaction phenotyping |
| what is checked ofr in cDDI and bioactivation risk assays | CYP450 inhibition and MDI |
| whats protein binding assays looking for and whats PgP looking for | plasma, blood, tissues(brain, liverl spleen) , micosomal, blood to plasma partioning pgp = hMDR1-MDCK |
| difference between doses in vitro and in vivo? | in vitro, almost full dose is available to interact with target in vivo - only small portion reaches biophase and can interact with target |
| what are the results from: 1)poor absorption or extenisive first pass metabolism 2)inappropriate distribution 3)large dist. vol/ tissue uptake 4) high protein binding 5) rapid systemic clearance | 1) no systemic exposure 2) doesn't reach target site 3)low circulating concentrations 4) low active concentrations 5) short duration of action |
| what is an ideal drug | oral and injectable( optimise oral bioavailability) once a day dosage ( plasma t 1/2) good penetration to the target( distribution) sufficient efficacy(optimise potency, duration and plasma protein binding) sufficient safety (selectivity) no drug-drug interactions |
| What should a target product profile include? | route of administration duration of treatment acceptability of side effects risk of cDDis cost of treatment (some need to cross blood brain barrier-) |
| what are 3 structural features that determines its physical props | lipophilicity (logP/ logD) solubility ionisation state |
| what will increasing charge, ionisation or hydrogen bonding capacity do to a molecule? | increase solubility but decrease permeability |
| what will increasing lipophilicity do ? | to some extent will increase permeability but decrease solubility |
| effects of increasing lipophilicity | increases oral absorption, plasma protein binding and volume of distribution. they can become more vulnerable to CYP450 metabolism --> to high clearance |
| what is renal clearance important for | hydrophilic compounds - therefore highly dependant upon lipophilicity |
| if logD7.4 is greater than 0 what is the renal clearance | (lipophilic compound) neglibable renal clearance (filtered by glomerulus but tubular reabsoption) |
| if LogD7.4 is less than 0 what is the renal clearance | (hydrophilic compound) extensive renal clearance (low reabsoption across tubule) |
| what are lipinskis rules | MW <500 daltons cLogP less than 5 H bond donors no more than 5 H bond acceptors (Ns and Os) no more than 10 |
| for monikas rules whats the acceptable rotatable bonds and | < 12 rotatable bonds and <110 polar surface |
| what is the general guide for lipophilicity when Log D7.4 is <1 | good solubility, low absorption and brain penetration, owing to low passive permeability. high clearance by kidney, due to polarity may exhibit paracellular permability if Mwt is low |
| what is the general guide for lipophilicity when Log D7.4 is between 1 and 3 | this is the ideal range, good intestinal absorption, owing to good balance of solubility and passive permeability. metabolism is minimised due to low binding to metabolic enzymes |
| what is the general guide for lipophilicity when Log D7.4 is between 3 and 5 | good permeability but absoption is lower due to lower solubility. metabolism is increased in this range due to increased binding to metabolic enzymes |
| what is the general guide for lipophilicity when Log D7.4 is >5 | low absorption and bioavailability due to low solubility. metabolic clearance is high because of high affinity for metabolic enzymes. Volume distrubtion and half life are high because compounds partition into and stay in tissues |
| what kind of drugs will passively cross a membrane? | unionised (neutral) |
| how do molecules diffuse through a lipid membrane | facilitated by 'shedding' H-bonded water molecules |
| what is polar surface area defined as | sum of squares of polar atom (usually Os a nd Ns) and their attached Hydrogens the bonding |
| Solubility is a determinant of | intestinal absorption and bioavailbility |
| how can solubility be increased | adding an ionisable group or reducing logP and Mwt |
| name 5 things that low solubility can result in | 1)poor absorption and bioavailability after oral dosing 2) insufficient solubility for IV dosing 3) artificially low activity values from bioassays 4)erratic assay results 5) development challenges (expensive formulations and increased development times) |
| what is kinetic solubility | the concentration of a compound in a solution when an induced precipitate first appears |
| name 4 kinetic solubility advantages | Identifying potential absorption and bioassay liabilities Diagnosing erratic bioassay results Developing generic formulations for animal dosing Developing structure-solubility relationships |
| how is a kinetic solubility tested | Compound initially dissolved in organic solvent eg DMSO then added to aqueous buffer Equilibrium not reached between dissolved and solid compound Conditions mimic discovery biological and property assays |
| name an advantage and 3 disadvanatges to kinetic aqueous solubility using laser nephelometry | +ve: allows fast high through put 'screening' approach to measuring aqueous solubility -ve:• Interference from contamination or fingerprints can skew accurate determination • As compound is already dissolved in solvent prior to addition of water (overcome crystal lattice energy) an increased solubility value may be determined. • Requires a significant amount of compound for testing. |
| name 7 strategies to increase solubility | • Ionisable group • Polar group • H-bond acceptor/ donor • Reduce logP • Reduce molecular weight • Reduce crystal packing • Prodrugs Modification of structure (eg addition of the water solubilising groups) must not be in a position which interferes with the pharmacophore, unless it can be made part of the pharmacophore |
| 8 strategies to improve permeability | • Ionizable group to non-ionizable group • Add lipophilicity • Isosteric replacement of polar groups • Esterify carboxylic acid • Reduce hydrogen bonding and polarity • Reduce Size • Add non-polar side chain • Pro-drug |
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