PHAR2210 exam

drug absorption

The movement of the drug from its site of administration to the systemic circulation.

paracellular and transcellular

what are the two ways for drugs to cross the lipid membrane from one compartment to another

it has a high affinity for calcium, and so accumulates in bones and teeth. can affect bone growth or lead to birth defects.

why are tetracyclines not used in pregnant people or young children?

describe the feature of thiopental which makes it appropriate for inducing anaesthesia, but not maintaining anaesthesia.

it is very lipophilic. due to blood flow, after administration it is first distributed into well perfused areas (liver and brain) and then slowly distributed into fat and muscle. if the drug is continuously infused, the drug will slowly accumulate in body fat but due to distribution being reversible, after it has stopped being administered, it will slowly return to systemic circulation. this could lead to hangover effects if it was used to maintain anaesthesia.

distribution

what pharmacokinetic process is responsible for the trends in this graph?

drug distribution

what does the pH of a body compartment influence

solute carrier transporters (SLC)

______ transport drugs via facilitated diffusion and active transport

facilitated, active

SLC’s transport drugs via ____ diffusion and _____ transport

ATP-binding cassette transporters (ABC)

______ transport drugs via active transport

MDR1, BCRP and MRP2

what are the three important efflux transporters that Caco-2 cells express?

apical, basolateral

top membrane is the _____ membrane and the bottom membrane is the _____ membrane

the apical membrane

in Caco-2 cells, the efflux transporters are located on which membrane?

how can you calculate drug efflux using caco-2 cells

By measuring the ratio of drug transported from the apical to basolateral side (B-A) to the drug transported from the basolateral to apical side (A-B). This is known as the efflux ratio (ER). The efflux ratio can be calculated using the following formula: ER = (B-A)/ (A-B).

by comparing the drug uptake and efflux in the knockout cells with the wild-type cells. If the drug uptake or efflux is significantly altered in the knockout cells, it suggests that the knocked-out transporter is involved in the drug transport.

How can you use transporter knockout Caco-2 cell lines to determine which drug transporter is involved with a drug?

which drug transporter is involved in the efflux of a particular drug

what can knocking out one or two of drug transporters in Caco-2 cell lines help to determine?

* as the ER for the WT cells is greater than 2, we can determine that these drugs undergo transporter-mediated efflux
* these two drugs are purely mediated by MDR1, and not BCRP or MRP2

what does this graph tell you about the efflux of the two drugs?

to determine what transporter is responsible for efflux of a drug

what is the purpose of transfecting cells with a transporter of interest

pH of compartment, blood flow, tissue binding, plasma protein binding, permeability of blood-tissue barrier, expression of transporters

list 4 of the 7 factors that influence drug distribution

basic

does alpha1 acid glycoprotein bind acidic or basic drugs?

acidic

does human serum albumin (HSA) bind acidic or basic drugs?

two

how many drug binding sites does each albumin contain?

fenestrations

what feature of the blood-tissue barrier allows exchange of molecules between the intravascular space and the interstitial fluid

endothelial cell layer and a basal membrane

list two features that the blood-tissue barrier and the blood-brain barrier share

glial cells that are connected by tight junctions

what is the extra protective feature that the blood-brain barrier has

to give more protection from harmful drugs

what is the function of glial cells in the blood-brain barrier

the liver

what is the first point of contact for orally administered drugs

more susceptible to toxicity

what is the side effect of being the first point of contact for orally administered drugs

single nucleotide polymorphism

what is one reason why there is variation in the response to drugs

brain tumour cells over express the same efflux transporters as the blood-brain barrier, so drugs can be returned to systemic circulation without reaching the brain.

why is it difficult for drugs to reach brain tumour cells

MDR1 and BCRP

give the two efflux transporters present at the blood-brain barrier.

\~60%

what percentage of body weight is the total body water.

high

when \[plasma\] is , volume of distribution is low.

oxidation, hydrolysis and dealkylation

what three processes are involved in phase 1 metabolism

phase 1 metabolism

what phase of metabolism: parent drug → metabolite(s)

oxygen atom added to parent drug OR hydrogen removed from a parent drug

describe oxidation in phase 1 metabolism

ethanol

what drug can be oxidised by having the hydrogen removed

codeine to morphine by CPYD2D6

give an example of a drug undergoing demethylation

hydrophilicity

does conjugation increase lipophilicity or hydrophilicity

glucuronidation

by what process is morphine metabolised into two conjugated metabolites, M3G and M6G

SULT transfers sulfonate group from PAPS to a drug or drug metabolite

give an overview of sulfation

morphine to morphine-3-glucuronide

give an example of pharmacologically active parent drug being converted into a pharmacologically inactive metabolite

morphine to morphine-6-glucuronide

give an example of pharmacologically active parent drug being converted into a pharmacologically active metabolite

paracetamol to NAPQI

give an example of pharmacologically active parent drug being converted into a toxic and reactive metabolite

codeine to morphine

give an example of prodrug being converted into a pharmacologically inactive metabolite

increases

drug metabolism _______ the molecular size of a drug

hydrophilic

______ drugs are excreted largely unmetabolised

decreased

how is the half life of a drug affected by drug metabolism

one atom goes to parent drug and the other goes to water molecule

what happens to each atom when O2 is used to metabolise CYPs

NADPH

what is the cofactor of CYPs

CYP2E1

which CYP is responsible for metabolism of paracetamol → NAPQI

UGT transfers glucuronic acid from UDP-glucuronic acid to the metabolite

describe the process of glucuronidation

extensive, metabolites

hepatic clearance drugs undergo ___ metabolism in the liver, and are excreted primarily as drug _______

low

do hepatically cleared drugs have high or low fe

parent, urine

renal clearance drugs are mainly excreted as __ drug in ___

high

do renally cleared drugs have a high or low fe

low

low fu results in ___ renal clearance