Impact of ABCB1 (MDR1) haplotypes on tacrolimus dosing in adult lung transplant patients who are CYP3A5 *3/*3 non-expressors.
BACKGROUND
The influence of ABCB1 (MDR1) polymorphisms on tacrolimus dosing has been questioned in previous studies with contradictory findings, possibly due to the association between CYP3A5 polymorphisms and tacrolimus dosing. The objective of this study was to assess the effect of ABCB1 haplotypes from 3 distinct polymorphic sites on the tacrolimus level/dose [L/D] in lung transplant patients limited to CYP3A5 *3/*3 non-expressors.


METHODS
A total of 91 lung transplant patients treated primarily with tacrolimus and prednisone were enrolled, and clinical information on drug dosing and blood levels was collected. The [L/D] was calculated for patients receiving tacrolimus at 1, 3, 6, 9 and 12 months post transplant. ABCB1 polymorphisms at C1236T, G2677T, and C3435T were assessed by PCR amplification and DNA sequencing. Haplotypes were estimated by Arlequin ver.2.00. Haplotype effects on tacrolimus [L/D] were assessed by two-way ANOVA.


RESULTS
Of the 10 haplotypes, CGC, TTT and CGT accounted for 44.1%, 40.7% and 7.6% of the total haplotypes, respectively. The tacrolimus [L/D] value in the CGC-CGC patients was significantly lower than in patients with CGC-TTT and TTT-TTT genotypes at the first month (mean [L/D]=1.45 versus 3.10 and 3.97 ngxmL(-)(1) /mg/day), and throughout the first post transplant year.


CONCLUSIONS
This study demonstrates that ABCB1 haplotypes derived from three common polymorphisms are associated with tacrolimus dosing in lung transplant patients when eliminating the confounder CYP3A5 genotype.
Wang
Jian
J
University of Southern California, 1985, Zonal Ave., PSC-100, Los Angeles, CA 90033, USA.
Zeevi
Adriana
A
McCurry
Kenneth
K
Schuetz
Erin
E
Zheng
Hongxia
H
Iacono
Aldo
A
McDade
Kevin
K
Zaldonis
Diana
D
Webber
Steven
S
Watanabe
Richard M
RM
Burckart
Gilbert J
GJ
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism; D000328:Adult; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000235:genetics*; D005260:Female; D006239:Haplotypes; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D016040:Lung Transplantation; D008297:Male; D027361:Organic Anion Transporters / Q000235:genetics* / Q000378:metabolism; D011110:Polymorphism, Genetic; D016559:Tacrolimus / Q000008:administration & dosage*; D013997:Time Factors
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D007166:Immunosuppressive Agents; D027361:Organic Anion Transporters; D003577:Cytochrome P-450 Enzyme System; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D016559:Tacrolimus