Pharmacokinetics aspects of ABC and SLOC transporters and Glucise-6-phosphate dehydrogenase polymorphisms Flashcards
What are ABC transporters?
Membrane proteins that couple substrate transport to ATP hydrolysis, functioning as either importers or exporters of substrates.
ABC transporters protect the body against xenobiotics and have physiological roles, such as bile transport in the liver and insulin regulation.
What are the two types of ABC transporters?
Importers and exporters.
Exporters include P-glycoprotein (P-gp) or MDR1, while importers are mainly found in prokaryotic species.
Where are ABC transporters typically expressed in cells?
On either the apical or basolateral side of polarized cells.
They are not expressed on both sides.
What role do ABC transporters play in drug circulation?
They interfere with drug circulation by pumping compounds back into the bloodstream.
What is P-glycoprotein (P-gp) also known as?
ABCB1.
What is the significance of the ABCB1 gene?
It is responsible for multi-drug resistance in cancer cells and was discovered in 2000.
Studies on polymorphisms of this gene have been conducted, although the functional consequences remain uncertain.
What are some locations where P-glycoprotein is expressed?
- Renal tubule brush border membranes
- Bile canniculi
- Astrocyte foot processes in the brain micro-vessels
- Gastrointestinal tract
What is the effect of polymorphisms in the ABCB1 gene?
They contribute to individual genetic variation and responsiveness to different drugs, leading to drug-drug interactions.
What condition is associated with the lack of MRP1 in Collie dogs?
Neurotoxicity from ivermectin.
Which polymorphisms are most commonly studied in the ABCB1 gene?
- Silent C1236T
- Ala393Ser (G2677T/A)
- Silent C3435T
What is the effect of the 3435G>T polymorphism?
It affects RNA stability.
What are the three common haplotypes of ABCB1?
- TTC
- CGT
- CGC
What did Wong D et al (2005) find regarding SNP 3435C>T?
It has been associated with decreased mRNA and protein levels via an unknown mechanism.
What effect do homozygotes of TT SNP have on P-gp transport activity?
Associated with increased P-gp transport activity.
What is the relationship between ABCB1 haplotypes and statin pharmacokinetics?
Haplotypes influence the pharmacokinetics of statins like simvastatin and atorvastatin.
What was the finding of Keskitalo et al (2008) regarding simvastatin and atorvastatin?
Patients with ABCB1 TTT/TTT genotype had larger AUC for simvastatin.
What are the implications of ABCG2 polymorphisms?
They can impair protein folding and reduce transport activity, leading to increased drug absorption.
What is the role of the SLOC1B1 gene?
Encodes OATP1B1, which transports anionic drugs into liver cells.
What is the effect of the Val174Ala polymorphism on pravastatin?
It affects the pharmacokinetics of pravastatin due to variations in transport activity.
True or False: ABC transporters can function as both importers and exporters.
False.
Fill in the blank: ABC transporters protect the body against _______.
xenobiotics.
What is a key function of P-glycoprotein in cancer cells?
Causes drug resistance.
How do polymorphisms in the ABCB1 gene affect drug metabolism?
They can lead to variations in drug response and efficacy.
What does the ABCG2 gene encode?
Breast cancer resistance protein (BCRP).
What is the significance of the C421A polymorphism in ABCG2?
It is a significant risk factor for the development of gout.
How does the ABCG2 genotype affect rosuvastatin pharmacokinetics?
Homozygous A/A allele may lead to higher concentrations of rosuvastatin.
What is fluvastatin classified as in relation to hepatic uptake transporters?
A lipophilic substrate of the hepatic uptake transporter organic anion transporting polypeptide 1B1 encoded by SLCO1B1.
What effect does the SLCO1B11B/15 genotype have on pravastatin clearance in Japanese subjects?
Significantly reduced oral clearance of pravastatin.
Which genotype in white German subjects is associated with a greater AUC of pravastatin?
1A/5 genotype.
What is the effect of the SLCO1B1 single-nucleotide polymorphisms (SNPs) g.−11187G>A and c.521T>C in white Finnish subjects?
Associated with an AUC of pravastatin that was increased by about 2-fold.
What is one of the most important strategies for the prevention and management of cardiovascular disease (CVD)?
Management of dyslipidemia with statins.
What is the global market sale of statins reported in 2014?
$28.5 billion.
What is a well-known variant of the SLCO1B1 gene that contributes to various haplotypes?
rs4149056 [c.521T>C (Val174Ala)].
What is the frequency of the SLCO1B1*5 allele in Europeans?
About 2%.
Which transporter does the SLC22A1 gene encode?
Cationic transporter OCT1 & OCT2.
What is the role of glucose-6-phosphate dehydrogenase (G6PD)?
Required to produce the antioxidant GSH (Glutathione).
What can low levels of GSH in erythrocytes lead to?
Haemolytic anaemia.
What is G6PDH deficiency?
A genetic defect affecting G6PDH, more common in males.
List one variant of G6PDH.
- A: Asp142Asn
- Mahidol: Gly163Ser
- Mediterranean: Ser188Phe
- Vanua Lava: Leu128Pro
- Viangchan: Val291Met
What class of G6PDH deficiency is associated with the most severe clinical severity?
Class 1.
Name a compound associated with drug-induced haemolysis.
- Nitrofurantoin
- Primaquine
- Sulphamethoxazole
- Acetanilide
- Naphthalene
True or False: There have been studies on the effects of SLCO1B1 polymorphism on the pharmacokinetics of fluvastatin.
False.
What does the study by Nguyen et al. (2023) focus on?
The association of variants of the SLCO1B1 gene with statin therapeutic efficacy.
What is the impact of poorly functional OATP1B1 gene on simvastatin concentration?
Increased concentration of simvastatin, which can lead to toxicity.
