Tacrolimus concentrations in relation to CYP3A and ABCB1 polymorphisms among solid organ transplant recipients in Korea.
BACKGROUND
Cytochrome P450 3A (CYP3A) and the drug transporter P-glycoprotein (P-gp) affect the bioavailability of tacrolimus, the most commonly used immunosuppressive agent in organ transplant recipients. We have determined the genotypic frequencies of the CYP3A and ATP-binding cassette sub-family B member 1 (ABCB1) genes, which encode the CYP3A and P-gp proteins, respectively, in Korean organ transplant recipients and donors, and have assessed the influence of CYP3A and ABCB1 polymorphisms on tacrolimus concentrations.


METHODS
Using chip-based MALDI-TOF mass spectrometry, 506 solid organ transplant recipients and 62 corresponding of liver transplant donors were genotyped for CYP3A4*6, CYP3A4*18, CYP3A5*3, CYP3A5P1*3, ABCB1 c.2677G>A/T, and ABCB1 c.3435C>T alleles, and their steady-state blood concentrations of tacrolimus were measured.


RESULTS
Frequencies of variant alleles among the transplant recipients were CYP3A5*3 76.8%, CYP3A5P1*3 75.9%, ABCB1 c.2677A/T 52.8%, ABCB1 c.3435T 36.9%, CYP3A4*18 1.9%, and CYP3A4*6 0.3%. The CYP3A5P1*3 allele was strongly linked to the CYP3A5*3 allele (r=0.816). Patients with the CYP3A5*3 and CYP3A5P1*3 alleles showed higher blood tacrolimus concentrations per adjusted dose ratio than did patients with wild-type alleles, among both liver transplant donors and renal transplant recipients.


CONCLUSIONS
The CYP3A5 genotype of the liver is considered to show the most important association with tacrolimus concentrations. Ultimately, genotyping for CYP3A5 may help optimal individualization of immunosuppressive drug therapy for patients undergoing solid organ transplantation.
Jun
Kyung Ran
KR
Department of Laboratory Medicine, Asan Medical Center and University of Ulsan College of Medicine, Seoul, Korea.
Lee
Woochang
W
Jang
Mi Sook
MS
Chun
Sail
S
Song
Gi-Won
GW
Park
Kwan Tae
KT
Lee
Sung Gyu
SG
Han
Duck Jong
DJ
Kang
Changwon
C
Cho
Dae-Yeon
DY
Kim
Jin Q
JQ
Min
Won-Ki
WK
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D017931:DNA Primers; D005787:Gene Frequency; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D007166:Immunosuppressive Agents / Q000097:blood* / Q000493:pharmacokinetics / Q000627:therapeutic use; D016030:Kidney Transplantation / Q000502:physiology*; D016031:Liver Transplantation / Q000502:physiology*; D016377:Organ Transplantation / Q000502:physiology*; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D016559:Tacrolimus / Q000097:blood* / Q000493:pharmacokinetics / Q000627:therapeutic use
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D017931:DNA Primers; D007166:Immunosuppressive Agents; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D016559:Tacrolimus