Flashcards in Chapter 4 - ABC Drug Transporters and Pharmacokinetics Deck (24):
name the three pharmacokinetic phases
name the two pharmacokinetic effectors
what are the possible in vivo problems with a new lead after it has been shown to work well in vitro?
1. low oral uptake
2. limited distribution to target tissue
3. rapid excretion/ degredation
4. severe side effects (toxicity)
Once a new lead has been shown to work in vitro, what are the next steps?
optimise physicochemical properties
specific: interaction with transporters and enzymes
Give three examples of ATP binding cassette efflux drug transporters
name 4 features of an ABC efflux drug transporter
1. in plasma membrane
3. catalyse efflux
4. broad substrate specificity
what is the function of the transmembrane domain of a ABC efflux drug transporter
1. drug binding and translocation pathway
2. provide alternating access
what is the function of the non-binding domain of a ABC efflux drug transporter
1. ATP binding and hydrolysis
2. form NBD dimer with ATP and interface
what drives the conformational changes at TMDs of ABC efflux drug transporters
ATPase cycles in NBDs via NBD dimerisation
give 6 examples of ABCB1 substrates
1. Analgesic : morphine
2. taxane (cancer) : docetaxel
3. HIV protease inhibitor: indinavir
4. H2-receptor antagonist: cimetidine
5. Ca channel blocker: verapamil
6. corticosteroids: hydrocortisone
how can tumour cells have structually diverse multidrug resistance?
drugs are actively extruded from the cell by a multidrug transporter
leads to reduced accumulation of drugs in cell
how does ABC efflux drug transporters have such a broad substrate specificity?
flexibility of helices surrounding drug binding site
good transporter substrates have poor oral availability. what two factors are responsible for this?
high direct intestinal excretion
high liver mediated excretion
why are efflux transporters present in the intestine and liver?
limit exposure to xenobiotics
What is the relationship between oral availability and presence of ABCG2?
ABCG2 reduces oral uptake of substrates
why is the oral availability of cytotoxic anticancer drugs (e.g. topotecan IV) rarely feasible?
narrow therapeutic window
variable uptake (genetic)
how can interpatient variation be reduced/ oral uptake improved?
drug transporter inhibitor + cytotoxic drug
= better oral availability
what happens when ABCB1 knockout mice are administered a dose of ivermectin (antiparasitic agent) relative to wild-type mice under the same dose?
100 X higher [ivermectin] in brain of (-/-) mice
as well as ABCB1, what other ABC is in the BBB?
What is the physiological role of ABC efflux transporters at blood tissue barriers?
limit penetration of xenobiotics into sensitive organs
-protection from natural toxins
-limit efficacy of therapeutic drugs targeting CNS, fetus, lymphocytes, tumours
name an ABCB1 and ABCG2 inhibitor
[Elacridar] high in gut; low at tissue-blood barriers
give an AIDS treatment which uses a co-administrative ABC efflux inhibitor
Ritonavir (efflux transporter/ metabolising enzyme inhibitor) + lopinavir (HIV protease inhibitor)
name a drug, that when combines with a ABC efflux inhibitor causes co-administered drug toxicity