NF unit 4

principles in drug handling by the body- ADME/pharmacokinetics in drug development

drug development relies on their being some relationship between what two things?

concentration, effect

what underpins the relationship between concentration (dose) and effect

pharmacokinetics and pharmacodynamics

pharmacokinetics uses parameters to describe the relationship between dose and concentration but this relationship does what?

changes over time

pharmacodynamics is the relationship between?

concentration and effect

what does ADME stand for?

absorption, distribution, metabolism, excretion

what does distribution, metabolism and excretion fall under?

disposition

what is absorption?

process by which unchanged drug proceeds from absorptive barrier to circulatory system

what is distribution?

process of drug transfer from immediate post absorption site to tissues

what happens in metabolism?

chemical change occurs in the drug such that it is no longer the original administered agent

routes of drug administration

done

speed of delivery/action in different routes

done

what is principle 1 of ADME?

no matter how the drug is delivered to the body it will be handled the exact same way

what is principle 2 of ADME?

all processes occur concurrently

different quantitative measures of pharmacokinetics

done

linking of ADME and PK

done

route and formulation have a big impact on absorption

the following remain constant across the profiles disregarding the rate of absorption:

• — of drug

• extent of —

• — processes of drug in the body itself

only different is in rate of absorption

faster the rate of absorption- the higher the peak — (—) and shorter time to — (shorter —)

dose, bioavailability, disposition, concentration, Cmax, Cmax, Tmax

use of multiple repeat dosing and how it can provide a steady state

done

use of therapeutic window and use in designing dosing regimens

done

what are the main 5 types of “biological barriers” in ADME?

epithelial barriers, capillary endothelial barriers, plasma membrane barriers, metabolism by enzymes, transport mediate membrane permeation

purpose of epithelial and endothelial barriers

done

what type of diffusion does hydrophobic molecules undergo

transcellular

what about hydrophilic

paracellular

effect of drug being weak acid or weak base on ionisation and pKa

done

pH variation around the body and within the intestinal tract

done

crossing an epithelial/endothelial barrier

done

how many phases of metabolism are there?

2

what is phase 1 metabolism?

oxidation reactions

what does phase 1 involve

functional group additions

what is phase 2 metabolism?

conjugation reactions

what does this involve

adding bulk

excretion involves physical removal of metabolites and parent drug- not chemical conversion

main mechanisms:

renal including:

• — as passive filtration mechanism

• — in renal tubules carrying drug from blood into tubule of the —

  • this is the — —

biliary secretion including

• active transport of drug from — into the — — with delivery to the — — and release into the —

GFR, transporters, nephron, urine flow, hepatocyte, biliary canaliculi, gall bladder, intestine

where are CYP450s expressed? (enzyme superfamily)

endoplasmic reticulum

polymorphism in CYP450S

done

example of DDIs arising from inhibition of CYP450

done

go watch a video going over glomerular filtration

done

what is a byproduct of muscle metabolism?

creatinine

creatinine is removed — from plasma by — —. little or no — — of creatinine occurs

if filtration in the kidney is deficient serum creatinine levels —

unchanged, glomerular filtration, tubular reabsorption, rise

creatinine clearance calculator

done

what is the equation for the overall excretion of drug in urine

(glomerular filtration- active tubular reabsorption) + active tubular secretion

where are the two major sites of solute absorption in the GI tract?

jejunum, ileum

what is the small intestine covered by?

enterocytes

extent of bioavailability in GI tract

done

definition of solubility

property of a solid to dissolve in a liquid to form a homogenous solution

permeability definition

intrinsic property of a membrane to allow passage of a solute

what is expressed on luminal (apical) membrane of intestinal epithelial cells?

P-gp

what is P-gp’s function

efflux drug back into the lumen of the intestine in the opposing direction for absorption into the body

when is a drug considered highly soluble?

highest dose strength of medicine is soluble in 250ml or less of aqueous media over the pH range of 1-7.5

difference between rate and extent of bioavailability

done

rate of bioavailability from extravascular dose

done

extent of bioavailability from extravascular dose

done

what is the AUC for extent of bioavailability?

exposure to drug

what is the equation for units of AUC?

concentration x time