ATP-binding cassette subfamily B member 1 polymorphisms do not determine cyclosporin exposure, acute rejection or nephrotoxicity after heart transplantation.
BACKGROUND
We hypothesized that genetic variation of ATP-binding cassette subfamily B member 1 (ABCB1) that encodes P-glycoprotein (involved in the uptake of cyclosporin A [CsA]) contributes to trough drug concentrations and thereby to CsA's immunosuppressive and toxic effects.


METHODS
Three hundred thirty-seven adult heart transplant recipients were studied retrospectively. White recipients receiving CsA at month 3 and years 1 to 5 after transplantation (n=192, 168, 156, 130, 95, and 74, respectively) were then studied with respect to ABCB1 genotype or haplotype and CsA disposition. Genotyping was performed using a gel-based polymerase chain reaction method. Dose- and weight-adjusted CsA trough concentrations ([microg/L]/[mg/kg]), time to first endomyocardial biopsy-proven acute rejection episode (grade>or=3A), weaning from steroids at 1 year, and renal function at 1 year posttransplant were measured.


RESULTS
An association between dose- and weight-adjusted CsA trough concentrations and ABCB1 haplotypes was found, with 12/1236, 21/2677, 26/3435 CC/GG/CC individuals having significantly higher concentrations than TT/TT/TT individuals at years 1 and 5 (68.9+/-26.9 vs. 54.9+/-19.5 and 70.6+/-35 vs. 50.0+/-12.2 [microg/L]/[mg/kg] P<0.05, respectively) There was no difference in the incidence of acute rejection, steroid weaning, or renal impairment between the genotype or haplotype groups.


CONCLUSIONS
The association of ABCB1 12/1236, 21/2677, and 26/3435 CC/GG/CC haplotype with increased CsA dose- and weight-adjusted CsA trough concentrations in this group of adult white heart transplant recipients was not consistent over time and had no effect on the incidence of acute rejection or on the development of renal impairment.
Taegtmeyer
Anne B
AB
Transplant Unit, Royal Brompton and Harefield NHS Trust, Harefield Hospital, Harefield, Middlesex, United Kingdom.
Breen
Jane B
JB
Smith
John
J
Burke
Margaret
M
Leaver
Neil
N
Pantelidis
Panagiotis
P
Lyster
Haifa
H
Yacoub
Magdi H
MH
Barton
Paul J R
PJ
Banner
Nicholas R
NR
D064286:ATP Binding Cassette Transporter 1; D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics*; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000368:Aged; D016572:Cyclosporine / Q000493:pharmacokinetics / Q000627:therapeutic use*; D005260:Female; D005838:Genotype; D006084:Graft Rejection / Q000453:epidemiology*; D016027:Heart Transplantation / Q000009:adverse effects / Q000276:immunology*; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D011237:Predictive Value of Tests; D012189:Retrospective Studies; D055815:Young Adult
D064286:ATP Binding Cassette Transporter 1; D018435:ATP Binding Cassette Transporter, Subfamily B; D018528:ATP-Binding Cassette Transporters; D007166:Immunosuppressive Agents; D016572:Cyclosporine