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Questions and Answers
Patient X has a genetic variant in ABCB2, while Patient Y has normal ABCB2 expression. If both patients are prescribed tenofovir, what is the most likely outcome?
Patient X has a genetic variant in ABCB2, while Patient Y has normal ABCB2 expression. If both patients are prescribed tenofovir, what is the most likely outcome?
- Patient X will not transport tenofovir out of kidney proximal tubule cells as effectively as Patient Y, potentially causing drug accumulation and toxicity. (correct)
- Patient X will excrete tenofovir more efficiently, leading to lower drug levels and reduced efficacy compared to Patient Y.
- Both patients will have similar tenofovir plasma concentrations and responses because ABCB2 is not clinically relevant for tenofovir.
- Patient X will experience decreased tenofovir absorption, resulting in lower drug levels and reduced efficacy compared to Patient Y.
Individual JR has SLCO1B1 *1/*1 genotype, while KT has SLCO1B1 *5/*5. If both start simvastatin, what is the likely outcome for KT compared to JR?
Individual JR has SLCO1B1 *1/*1 genotype, while KT has SLCO1B1 *5/*5. If both start simvastatin, what is the likely outcome for KT compared to JR?
- KT will experience increased efficacy and a decreased risk of side effects from simvastatin compared to JR.
- KT will experience increased efficacy and an increased risk of side effects from simvastatin compared to JR.
- KT will experience decreased efficacy and an increased risk of side effects from simvastatin compared to JR. (correct)
- KT will experience reduced efficacy and a decreased risk of side effects from simvastatin compared to JR.
Two post-transplant patients are initiated on tacrolimus. Patient A is CYP3A5*1/1 and ABCB1 3435TT, while Patient B is CYP3A53/*3 and ABCB1 3435TT. Assuming similar clinical and demographic factors, what is the expected difference in tacrolimus response?
Two post-transplant patients are initiated on tacrolimus. Patient A is CYP3A5*1/1 and ABCB1 3435TT, while Patient B is CYP3A53/*3 and ABCB1 3435TT. Assuming similar clinical and demographic factors, what is the expected difference in tacrolimus response?
- Patient A will likely require higher tacrolimus doses due to increased drug metabolism compared to Patient B. (correct)
- Both patients will likely require similar tacrolimus doses due to the ABCB1 genotype outweighing the CYP3A5 genotype.
- Patient B will likely require higher tacrolimus doses due to increased drug metabolism compared to Patient A.
- Patient A will likely require lower tacrolimus doses due to decreased drug metabolism compared to Patient B.
Which of the following mechanisms involving intestinal transporters would MOST likely result in decreased drug exposure (AUC)?
Which of the following mechanisms involving intestinal transporters would MOST likely result in decreased drug exposure (AUC)?
A patient is experiencing liver injury related to bile acid accumulation. Which of the following transporter-related issues could be a potential cause?
A patient is experiencing liver injury related to bile acid accumulation. Which of the following transporter-related issues could be a potential cause?
Simvastatin relies on OATP1B1 to enter hepatocytes. A patient with the SLCO1B1 c.521T>C polymorphism, which reduces OATP1B1 activity, is prescribed simvastatin. What is a likely clinical consequence?
Simvastatin relies on OATP1B1 to enter hepatocytes. A patient with the SLCO1B1 c.521T>C polymorphism, which reduces OATP1B1 activity, is prescribed simvastatin. What is a likely clinical consequence?
Which statement below is INCORRECT regarding drug transporters and their clinical relevance?
Which statement below is INCORRECT regarding drug transporters and their clinical relevance?
A graph shows the area under the curve (AUC) for fexofenadine. One line (dotted) shows higher AUC values compared to another line (solid black). Which of the following is the MOST accurate interpretation?
A graph shows the area under the curve (AUC) for fexofenadine. One line (dotted) shows higher AUC values compared to another line (solid black). Which of the following is the MOST accurate interpretation?
Which of the following scenarios correctly pairs a transporter type and location with the effect of decreased function on drug AUC?
Which of the following scenarios correctly pairs a transporter type and location with the effect of decreased function on drug AUC?
Individuals of _____ ancestry have a higher prevalence of the ABCG2 variant compared to _____ and _____ ancestries.
Individuals of _____ ancestry have a higher prevalence of the ABCG2 variant compared to _____ and _____ ancestries.
Genetic variation in the _____ transporter can result in an accumulation of _____ and lead to liver injury.
Genetic variation in the _____ transporter can result in an accumulation of _____ and lead to liver injury.
_______ is an influx drug transporter on the apical membrane of the intestinal endothelial cell. Fexofenadine is a substrate of this transporter, and the transporter activity is _______ by grapefruit juice. If grapefruit juice is taken with fexofenadine, the absorption of fexofenadine will be ______, resulting in ______ fexofenadine AUC.
_______ is an influx drug transporter on the apical membrane of the intestinal endothelial cell. Fexofenadine is a substrate of this transporter, and the transporter activity is _______ by grapefruit juice. If grapefruit juice is taken with fexofenadine, the absorption of fexofenadine will be ______, resulting in ______ fexofenadine AUC.
OATP1A2 is a drug transporter in the intestinal wall, and its activity is _______ by grapefruit juice. Fexofenadine, a substrate of OATP1A2, absorption is _______ by grapefruit juice, resulting in __________ fexofenadine AUC.
OATP1A2 is a drug transporter in the intestinal wall, and its activity is _______ by grapefruit juice. Fexofenadine, a substrate of OATP1A2, absorption is _______ by grapefruit juice, resulting in __________ fexofenadine AUC.
Ritonavir-boosted therapy and the combined administration of penicillin and probenecid are examples of beneficial drug-drug interactions.
Ritonavir-boosted therapy and the combined administration of penicillin and probenecid are examples of beneficial drug-drug interactions.
Flashcards
ABCB2 Transporter
ABCB2 Transporter
A drug transporter that transports tenofovir out of kidney cells into the urine for elimination. Reduced expression leads to drug accumulation and potential toxicity.
SLCO1B1 *5/*5
SLCO1B1 *5/*5
A genetic polymorphism that results in decreased OATPB1B1 activity, leading to reduced simvastatin transport into hepatocytes and increased plasma concentrations of simvastatin, increasing risk of side effects and decreasing efficacy.
CYP3A5*1/*1 Effect on Tacrolimus
CYP3A5*1/*1 Effect on Tacrolimus
Patients with CYP3A5 expressers (*1/*1) exhibit lower tacrolimus concentrations and typically need higher doses.
Effect of Uptake Transporter Polymorphism
Effect of Uptake Transporter Polymorphism
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Cause of Liver Injury via Bile Acid Accumulation
Cause of Liver Injury via Bile Acid Accumulation
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SLCO1B1 c.521T > C Clinical Result
SLCO1B1 c.521T > C Clinical Result
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Drug Transporters
Drug Transporters
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OATP1A2 Function Effect
OATP1A2 Function Effect
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Endothelial Cell Efflux Transporter Effect
Endothelial Cell Efflux Transporter Effect
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ABCG2 Variant Prevalence
ABCG2 Variant Prevalence
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BSEP (ABCB11) Dysfunction
BSEP (ABCB11) Dysfunction
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OATP1A2 and Grapefruit Juice
OATP1A2 and Grapefruit Juice
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Beneficial Drug-Drug interactions
Beneficial Drug-Drug interactions
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Study Notes
- Study notes on pharmacogenomics, drug transporters, and drug interactions
ABCB2 Transporter
- ABCB2 is an efflux transporter located on the apical membrane of kidney proximal tubule cells.
- In patients with ABCB2 variants:
- Reduced transporter expression leads to decreased drug elimination.
- Can result in drug accumulation and potential toxicity.
- Example with tenofovir:
- Patient A with ABCB2 variant will have less tenofovir transported out of kidney cells.
- Patient A experiences drug accumulation and higher toxicity.
- Patient B with normal ABCB2 will eliminate tenofovir more efficiently.
SLCO1B1 and Simvastatin
- SLCO1B1 impacts simvastatin transport into hepatocytes.
- JR with SLCO1B1 *1/*1: normal function
- KT with SLCO1B1 *5/*5: decreased OATP1B1 activity
- KT taking simvastatin:
- Increased risk of side effects.
- Decreased efficacy of simvastatin.
- Reduced simvastatin transport into hepatocytes, leading to increased plasma concentrations and statin-induced myopathy.
CYP3A5, ABCB1, and Tacrolimus
- Patient A: CYP3A5*1/*1 and ABCB1 3435TT
- Patient B: CYP3A5*3/*3 and ABCB1 3435TT
- Patient A (CYP3A5 expresser) expected to have lower tacrolimus concentrations.
- Requires higher doses compared to Patient B.
- Tacrolimus concentrations and doses are associated with CYP3A5 genotype.
Intestinal Transport and Drug Exposure
- Decreased drug exposure (AUC) can be caused by:
- Polymorphism resulting in decreased activity of an intestinal uptake transporter.
- A polymorphism resulting in an intestinal efflux pump with decreased activity will NOT cause decreased drug exposure
- Drug inhibition of an intestinal efflux pump will NOT cause decreased drug exposure
- Drug induction of intestinal uptake transporters will NOT cause decreased drug exposure.
Liver Injury and Bile Acid Accumulation
- Nonfunctional polymorphism of an efflux pump into the bile canaliculus can cause liver injury.
- Bile acids accumulate in the liver due to impaired efflux.
- Drug inhibition of efflux pumps lining the bile canaliculus prevents bile acids from exiting the liver causing liver injury
SLCO1B1 c.521T>C and Simvastatin
- SLCO1B1 c.521T > C polymorphism results in decreased OATPB1B1 activity.
- Clinically, this results in increased side effects of simvastatin.
- higher risk of myopathy.
Drug Transporters and Clinical Relevance
- Most drugs are substrates of more than one transporter.
- It is false that most drugs are transported by a single carrier protein.
- Transporters are classified by mechanism and genetic sequence.
- A single nucleotide polymorphism can alter drug pharmacokinetics.
OATP1A2 Function
- The solid black line represents poor function OATP1A2
- The dotted line represents normal function OATP1A2
- Fexofenadine is a substrate for the OATP1A2 transporter, which is an influx transporter on the apical side of the enterocyte.
- Decreased function of the transporter will lead to decreased fexofenadine absorption and decreased AUC concentrations.
Transporter Type and AUC
- Endothelial cell efflux transporter on basolateral side with decreased function leads to decreased AUC.
- Decreased function of influx transporters on the apical side results in decreased AUC
- Increased function of efflux transporters on the apical side results in decreased AUC
ABCG2 Variant Prevalence
- East Asian ancestry has a higher prevalence of the ABCG2 variant.
- The ABCG2 variant is least common amongst European ancestry
Genetic Variation and Liver Injury
- Genetic variation in the BSEP (ABCB11) transporter results in accumulation of bile acids.
- Leads to liver injury.
- BSEP is an efflux transporter in the liver.
- BSEP is responsible for removing bile acids.
OATP1A2, Fexofenadine, and Grapefruit Juice
- OATP1A2 is an influx drug transporter on the apical membrane of the intestine endothelial cell.
- Fexofenadine is a substrate of OATP1A2.
- OATP1A2 transporter activity is inhibited by grapefruit juice.
- Grapefruit juice taken with fexofenadine will decrease absorption.
- Resulting in decreased fexofenadine AUC.
OATP1A2 and Grapefruit Juice
- OATP1A2 activity is inhibited by Grapefruit Juice.
- Fexofenadine absorption is decreased by Grapefruit Juice.
- Results in decreased fexofenadine AUC.
Beneficial Drug-Drug Interactions
- Ritonavir-boosted therapy and combined penicillin/probenecid are examples of beneficial drug-drug interactions.
- Low-dose ritonavir decreases metabolism of other HIV Protease Inhibitors by CYP3A4.
- Probenecid inhibits renal secretion of penicillin, increasing its plasma concentration.
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