Genetics of ABC and SLCO drug transporters Flashcards
How many introns and exons are in the ABCB1 gene normally and what does it encode for
28, 28
P-glycoprotien
what are the three most common polymorphims of the ABCB1 gene
Exon 12: Silent C1236T
Exon 21: Ala393Ser G2677T/A
Exon 26: Silent C3435T
what are the three most common haplotypes of ABCB1 gene
TTC
CGT
CGC
what is the overall proposed effecr of allele varients for the ABCB1 gene
- that some variants result in reduced transport capacity and thus reduced drug efflux
- this is either by changes to mRNA and protein expression and stability or by changes to transport activity and substrate specificity
what gene is responsible for the significant difference between haplotypes for the response of simvastatin
ABCB1
which haplotype of ABCB1 causes an significant increase in AUC when simvastatin is administered
TTT
what two measurement are increased if a person who possesses the TTT haplotype receives atorvastatin compared to a person with CGC haplotype
T1/2 and AUG
which ABCB1 polymorphisms cause a significant decrease in total cholesterol and LDL cholesterol
1236 C>T
2677 G>A/T
The presence of which genotype in all three ABCB1 polymorphisms __ the risk of SAMS almost twofold
TT
increased
what does SAMS
statin associated muscle syndrome = myalgia
true or false - Differences of ABCB1 haplotypes has a significant effect on the pharmacokinetics of fluvastatin, pravastatin, lovastatin, and rosuvastatin.
false
true or false - Human MDR1 polymorphism: G2677T/A and C3435T have no effect on MDR1 transport activities.
true
what does the ABCG2 do
drug absorption and biliary excretion
physiological role in uric acid excretion
Normally limits drug absorption
what is the most frequent ABCG2 polymorphisms
421 C>A
what is the allele frequency of the ethnicity’s for ABCG2 (421 C>A)
Asians - 29-36%
Europeans - 4.5-12%
African - 0-2.3%
whats is the Amino acid change of ABCG2 (421C>A) and what is the risk factor associated
Gln141Lys, Risk factor for gout
what is the effect of ABCG2 421C>A on the protien
- Impaired protein folding and cellular processing
- Protein expression in the cell membrane reduced by 30-40%
- Reduced transport activity (by >20% in vivo)
-> Reduced efflux and increased drug absorption
what is the effect of the ABCG2 polymorphim on Rosuvastatin
- Normal pumps a large proportion of the drug back into the lumen of the small intestines
- Individuals with the polymorphism will have lower BCRP protein conc
- Cmax and area under the curve (AUC) significantly higher in A/A compared to C/C
what does high concentration of Rosuvastatin cause in the body
increases the risk of muscle toxicity
what does the SLCO1B1 gene encode
organic anion transporter 1B1
-especially hydrophilic compounds, into liver reducing systemic availability
what is the effect of SLCO1B1*5
lead to decreased transport
Val174Ala
has 3-fold lower Vmax
what two amino acid substitutions increases transport activity in SLCO1B1
*14 = Pro155Thr -(C463A)
*20 = Leu643Phe (A1929C)
What is effect of SLCO1B1*5 on pravastatin
- CC haplotype (variant) causes a higher plasma concentration of pravastatin
If were were using genotype to predict OATPC function, who would have highly increased function ?
Homozygous for either *14 or *20
