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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 |
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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. |
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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. |
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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. |
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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) |
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MDR involving the ATP-binding cassette family include ____ and the _____ in tumor cells. |
P-gp MRP - multidrug resistant protein |
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MRPs are efflux pumps that transport _________. MRP1 and MRP2 are specific for _______. |
organic anion drug conjugates AND intact drug conjugates (glucoronide and glutathione ocnjugates) |
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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 |
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In hepatocytes... While uptake transporters are located on the ______ membrane, efflux proteins are found on the _____ memberane |
Basolateral/sinusoidal Apical/canalicular |
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_____ 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 |
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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) |
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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 |
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T or F Drugs that are inhibitors of p-gp can eventually become inducers |
true |
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Paclitaxel is a substrate of ____ and _____ and is metabolized mainly by ________. It follows ____ kinetics |
P-gp and CYP (3A4 and 2C8) hydroxylation. Non-linear |
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Co-administering _____ with paclitaxel can increase F from 5% to 50% and avoids the toxicity associated with the vehicle in the IV formulation |
cyclosporinA |
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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% |
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_____ is the most abundant form of antibody, comprising 85% of the immunoglobulin system. |
IgG |
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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. |
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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. |
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What is a xenomouse? |
A mouse that only produces human IgG antibodies |
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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 |
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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 |
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For glycoproteins like tPA and IgG, ______ often serve as recognition sites for carrier mediated hepatic uptake |
sugar moeities |
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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 |
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Differentiate between mechanism dependent and independent toxicities of mAB therapy |
independent: hypersensitivity dependent: result from binding to target. Ex: cardiotoxicity with trastuzumab |
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Which of the aromatase inhibitors had no impact on plasma lipid levels? |
Anastrozole |
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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 |
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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 |
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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 |
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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 |
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What processes occur during tmoxifen metabolism? |
Hydroxylation and N-demethylation via CYP enzymes. |
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The major urinary metabolite of 5-FU is ______, which is formed in the _____ and ________ tissues. |
FBAL liver and extrahepatic tissues |
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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) |
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How does 5-FU gain access to the cell? Where does DPD act? |
saturable carrier mediated transport DPD metabolized 5-FU outside the cell |
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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 |
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What are DIFs? |
DPD inhibitory fluoropyrimidines examples: tegafur/uracil or eniluracil/5-FU |
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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) |
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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 |
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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 |
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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 |
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Epotin alfa is a recombinant DNA glycoprotein from hamster cells that weighs ______ kDA |
30K |
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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 |
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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. |
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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% |