• Shuffle
    Toggle On
    Toggle Off
  • Alphabetize
    Toggle On
    Toggle Off
  • Front First
    Toggle On
    Toggle Off
  • Both Sides
    Toggle On
    Toggle Off
  • Read
    Toggle On
    Toggle Off
Reading...
Front

Card Range To Study

through

image

Play button

image

Play button

image

Progress

1/44

Click to flip

Use LEFT and RIGHT arrow keys to navigate between flashcards;

Use UP and DOWN arrow keys to flip the card;

H to show hint;

A reads text to speech;

44 Cards in this Set

  • Front
  • Back

______ is a term used to describe the ability of drug resistant tumors to exhibit simultaneous resistance to a number of unrelated chemo agents.

Multidrug resistance

MDR can be non-cellular or cellular based. Give examples for conditions associated with non-cellular resistance in solid tumors

Poor vascularization


Tumor not dividing quickly enough


high lactic acid content (low pH) means less cellular uptake.

How does GST contribute to non-classical MDR?

GST is overexpressed in tumor cells. Protects the cell from epoxides and is involved in metabolic biotransformation of cytotoxic drugs. Drugs conjugated by glutathione are excreted in the urine as a mercaputuric acid derivative.

Topoisomerase is another non-classical MDR phenotype. It is thought to be due to either under-expression of the enzyme or over-expression of P-gp. Name an approach to overcome MDR related to topoisomerase?

Administer both types I and II inhibitors together. Ex: irinotecan AND doxorubicin.

The following relates to non-classical MDR phenotype of altered apoptosis.




Tumor cells lacking ____ gene or exhibiting over-expression of _____ gene increase resistance to anticancer drugs or radiation

p-53 (tumor suppressor)




BCL-2 ( block cell death)

MDR involving the ATP-binding cassette family include ____ and the _____ in tumor cells.

P-gp


MRP - multidrug resistant protein

MRPs are efflux pumps that transport _________. MRP1 and MRP2 are specific for _______.

organic anion drug conjugates AND intact drug




conjugates (glucoronide and glutathione ocnjugates)

The main isoforms of p-gp in humans is called _______. P-gp is a efflux protein for _____ molecules.

MDR1a and MDR1b




manily organic cations and neutral molecules

In hepatocytes...


While uptake transporters are located on the ______ membrane, efflux proteins are found on the _____ memberane

Basolateral/sinusoidal




Apical/canalicular

_____ is a chemo drug that induces P-gp abd lowers oral bioavailability. _____ is a p-gp transporter blocker that can increase F.

cisplatin




cyclosporin A

Administration of MDR modulators for p-gp can alter biliary excretion by the ______ and ______ clearance by the kindey of anticancer drugs

Liver and renal




P-gp is located in the liver (canicular membrane) and in the kidney (brush border)

Name an example of a drug combination that could provide increased selectivity for cancer chemotherapy (hint: consider leaky walls of tumor cells)

nano particles (liposomes) couples with p-gp inhibitors can offer another approach to taregt therapy

T or F




Drugs that are inhibitors of p-gp can eventually become inducers

true

Paclitaxel is a substrate of ____ and _____ and is metabolized mainly by ________. It follows ____ kinetics

P-gp and CYP (3A4 and 2C8)


hydroxylation.


Non-linear

Co-administering _____ with paclitaxel can increase F from 5% to 50% and avoids the toxicity associated with the vehicle in the IV formulation

cyclosporinA

T or F


The incidence of inducing an immune response is less with a humanized vs. chimeric biologic agent. GIve an example.

T




infliximab has 10% immunigenicity while adalimumab has 5%

_____ is the most abundant form of antibody, comprising 85% of the immunoglobulin system.

IgG

How was mouse monoclonal antibody production achieved?

Murine spleen cell and human myeloma cell were fused to form a hybridoma cell line, which is reinfected into the mouse.

How is production of chimerical monoclonal antibodies achieved?

The variable mouse regions (both VL and VH) from a mouse cell are inserted into a plasmid vector containing the human constant region sequence and put back into a myeloma cell. The antibody secreted by these cells is now chimeric.

What is a xenomouse?

A mouse that only produces human IgG antibodies

Absorption of antibodies following SC/IM admin is through the ____________, which has a cutoff minimum of 20 kDa.




The Tmax of antibodies given in this route is ____ days.

lymphatic system




1-8 days

Because of their large size, proteins have a _____ Vd. They access cells through ______ and are transported through the ____ system

small - equal to or slightly larger than total plasma volume (<0.1L/kg)




receptor mediated uptake




lymphatic

For glycoproteins like tPA and IgG, ______ often serve as recognition sites for carrier mediated hepatic uptake

sugar moeities

Because of their size, MABs aren't excreted into the urine but are metabolized in various tissues and in plasma. Name a few of these degradation methids

- proteolysis by liver and RES


- target-mediated elimination by phagocytic cells


-nonspecific endocytosis follow byd egradation in lysosomes

Differentiate between mechanism dependent and independent toxicities of mAB therapy

independent: hypersensitivity


dependent: result from binding to target. Ex: cardiotoxicity with trastuzumab

Which of the aromatase inhibitors had no impact on plasma lipid levels?

Anastrozole

a) Which of the 3 AIs has he longest half life and Tss?




b) Which category of AI has higher suppression of plasma estrogen compared to baselines?




c) Which of the 3 AIs is not known to be an inhibitor of CYPs but has androgenic properties?

a) Letrozole




b) nonsteroidal (anastrozole and letrozole)




c) exemestane

Which two SERMs have longer half lives and consequently, longer Tss than the other agents?

Tamoxifen and toremifene (5-7 days T1/2) and several weeks for Tss

When comparing tamoxifen, toremifene, and raloxifene, which SERM has the most drug interactions?

Tamoxifen!




Interacts with warfarin, rifampin, aminoglutethimide and letrozole




Avoid taking CYP2D6 inhibitors - SSRIs

T or F




Tamoxifene is believed to be a pro-drug that is metabolized to endoxifen. Small amounts of tamoxifen are actually converted to the active metabolite

true

What processes occur during tmoxifen metabolism?

Hydroxylation and N-demethylation via CYP enzymes.

The major urinary metabolite of 5-FU is ______, which is formed in the _____ and ________ tissues.

FBAL


liver and extrahepatic tissues

A) What type of kinetics does 5-FU obey?




B) What is the half-life?




C) Is it a low or high clearance drug?

a) nonlinear (t1/2, Cl, and Vd are dose-dependent - saturable kinetics)




b) 17 minutes




c) high clearance (more than half liver blood flow)

How does 5-FU gain access to the cell? Where does DPD act?

saturable carrier mediated transport




DPD metabolized 5-FU outside the cell

When a DPD inhibitor is give, what parameters are altered?

half life is longer


clearance is lower


vd is larger


prodrug to metabolite ration increases

What are DIFs?

DPD inhibitory fluoropyrimidines




examples: tegafur/uracil or eniluracil/5-FU

A) Describe the F of imatinib




B) half life




c) PBP



D)How is imatinib metabolized?




E) excretion

A) 98%




B) 18 hours




C) highly




D) 3A4/3A5 by N-dealkylation. It also inhibits CYP3A4/5




E) in bile as active metabolites. (CGP 74588)

Describe some trends for the PK of the TKIs

- high F (unknown for some)


- fast oral absorption (short tmax)


- high PBB and Vd


- long t1/2, except dasatinib (3-5 hours)


- metbolized primarily by CYP3A4


- predominantly excreted in feces


- time dependent inhibition (DIs)


- substrate for p-gp

PK of Abiraterone.




Considered a prodrug that is rapidly/completely metabolized by _____. It is bound ___% to plasma proteins. It is an inhibitor of ______ and _______. It's metabolized by ________ and _______ and ______ to inactive metabolites that get eliminate in the feces.

esterases


99%


p-gp, CYP1A2 and CYP2D6


CYP3A4, SULT, UGT

Should abiraterone be given with food?

No - food significantly increases absorption so it should be taken on an empty stomach to avoid variations in absorption

Epotin alfa is a recombinant DNA glycoprotein from hamster cells that weighs ______ kDA

30K

A) Is the Vd of eppoetin alfa small or large?




B) Clearance?




C) F for SC vs. IC?

A) small (<Lk/kg)


B) small


C) 50%




The site of injection, muscle actvitity, and physical condition could influence the rate and extent of absorption

How do sialic acid residues affect the half life of epotein alfa?

Epotein is mostly metabolized (95%). Removal of the sialic acid residues decreases half life from 2 hours to 10 minutes! Salic acid on the epotein structure prolongs half life. Unlike other cases with tpa or mABs where suagr moieties served as recognition sites for hepatocytes.

When epotein is given SUBQ as opposed to IV, the slow absorption allows us to decrease the total weekly MD by ___ to ____ %

23 to 52%