الفهرس 
ntroduction and Aim of the WorkOnly 14 pages are availabe for public view
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Abstract
Tacrolimus is a substrate of P-glycoprotein, the product of the
ATP-binding cassette transporter (ABCB1) gene, acts as an efflux
transporter that limits the oral absorption of drugs when P-gP
expression increases leading to increase transport of tacrolimus out of
the enterocytes. Genetic variability in the ABCB1 gene results in
inter-individual differences in its expression and activity. The most
studied ABCB1 gene polymorphism is 3435C>T. Wild type (CC)
genotype will help rapid transport, thus increase (Tac.) washing out of
the cells to the intestinal lumen so its blood trough concentration
decreases so patients need to increase the dose of the drug so, C/D
ratio decrease.
Gene polymorphism (6986A>G) in cytochrome P450 3A5 (CYP
3A5) is assumed to be the major factor that contributes to the
pharmacokinetic variability of tacrolimus. The presence of an A allele
at the polymorphic site in the CYP3A5 gene suggests that an
individual has a functionally active enzyme (expresser) and carries
one of the two genotypes (CYP 3A5*1*1 or CYP 3A5*1*3). By
contrast, non-expressers do not have a functionally active enzyme and
carry the CYP3A5 3*3 genotype. This finding suggests that CYP3A51
carriers are at higher risk of under‐immunosuppression
The aim of this study was to assess the influence of ABCB1 and
CYP3A5 genes polymorphism of both donors and recipients of liver
transplant patients on blood level and dose requirements of oral
tacrolimus in liver transplant recipients in an attempt to help in
designing an individualized tacrolimus regimen.
This pilot study was conducted on 48 adult patients who
underwent liver transplantation at liver transplant unit, National Liver Institute, Menoufia University in the period from January 2011 to July
2014, and their 48 donors, after transplantation, and they were
followed up for 6 months.
Liver transplant recipients were subjected to the following:
1- Full clinical history (age, gender and body weight in kg)
preoperatively
2- Laboratory investigations which was done preoperatively, 1 and
6 months postoperatively, which were:
a- Liver function tests: serum total and direct bilirubin
b- Kidney function tests (urea, creatinine and creatinine
clearance)
c- Random blood sugar level
3- Blood tacrolimus level was measured first, second, third days,
1, 2 weeks, 1, 3 and 6 months postoperatively using ultra
performance liquid chromatography tandem mass spectrometry
(UPLC MS/MS). The samples were taken as whole blood
samples; they were taken at 9 am at morning 2 hours before the
next (Tac.) dose.
All participants in the study were subjected to molecular testing
- ABCB1 genotyping by polymerase chain reaction (PCR) based
on restriction fragment length polymorphism (RFLP) assay
- CYP3A5 genotyping by Taqman real- time PCR.
The data was analyzed using a statistical computer program (SPSS).
The present study showed no significant difference between
recipients and donors regarding ABCB1 (3435 C>T) and CYP3A5
(6986 A>G) genotypes and alleles distribution.
• Concerning the recipients’ ABCB1 SNP, significant increase in
(Tac.) daily dose was observed among recipients carrying ABCB1 CC
genotypes during and after the first month after transplantation.
• There was decreased (Tac.) concentration in ABCB1 CC genotype
carrying recipients compared with those carrying T allele during the
first 2 weeks after transplantation.
• There was significantly increased (Tac.) C/D ratio in ABCB1 T
allele carrying recipients compared with those carrying CC genotype,
3 months post transplantation.
• Recipients carrying T allele and receiving graft from CC genotype
donors needed higher FK506 doses compared to those receiving T
allele grafts late postoperatively at 6 months when the graft became
fully functioning.
• The ABCB1 genotype of the graft affected the tacrolimus C/D ratios
at six months post operatively where lower ratio was detected in grafts
carrying the CC genotype compared to grafts with T allele regardless
of the recipients’ ABCB1 genotype as the transplanted liver became
fully functioning.
• Concerning the recipients CYP3A5 SNP, no significant increase in
(Tac.) daily dose was observed among recipients during the period of
the study.
There was significantly increased (Tac.) concentration in CYP3A5
3*3 carrying recipients compared with those carrying *1 allele during
the first 2 weeks post transplantation.
• There was significantly increased (Tac.) C/D ratio in CYP3A5 3*3
carrying recipients compared with those carrying *1allele during the
first 2 weeks after transplantation.
• Recipients engrafted with 3*3* genotype had higher (Tac.) C/D at
six months regardless of the recipients CYP3A5 genotype.