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.

Effect of adenosine monophosphate deaminase-1 C34T allele on the requirement for donor inotropic support and on the incidence of early graft dysfunction after cardiac transplantation.

The C34T T allele of the adenosine monophosphate deaminase-1 (AMPD1) gene has been associated with improved outcome in patients with cardiac dysfunction. We hypothesized that possession of this allele by donor hearts plays a role in the outcome of cardiac transplantation; 262 cardiac donors and 190 of their recipients were studied. AMPD1 C34T genotype was determined using 5' exonuclease chemistry. Requirement for inotropic agents before organ donation, 1-year post-transplantation survival, cause of death, and factors known to affect survival after transplantation were also studied. Multiple regression models for factors affecting survival were constructed. A significant yearly increase in frequency of the T allele in donors was noted (0.06 to 0.18 from 1994 to 1999). Donors with the CT or TT genotype required less inotropic support than those with the CC genotype (mean number of inotropes per donor with CT or TT genotype 0.27 compared with 0.47 per donor with CC genotype, n = 206, p = 0.03). Recipients of T-allele-carrying organs showed worse 1-year survival after transplantation (59% vs 79%, p <0.001). Excess deaths in these patients was due to early graft dysfunction (odds ratio for early graft dysfunction 6.6, 95% confidence interval 2 to 21.6, p = 0.0001). Multivariate analysis showed donor AMPD1 genotype, recipient age, and pretransplantation anemia to independently affect 1-year post-transplantation survival (adjusted hazard ratios 3.7, 1.06, and 2.6, respectively). In conclusion, possession of the AMPD1 T allele is associated with decreased inotropic requirements before heart donation. The incidence of early graft dysfunction, however, was significantly higher in recipients who received AMPD1 T-allele-possessing organs resulting in worse 1-year survival.

Pharmacokinetics of oral cyclosporine (Neoral) in heart transplant recipients during the immediate period after surgery.

Neoral cyclosporine has better absorption characteristics than the original Sandimmun formulation. This has allowed Neoral to be administered orally in circumstances where Sandimmun had been ineffective, including the postoperative phase of liver transplantation. Sampling strategies, such as the measurement of drug concentration 2 h after oral administration, have been used in a variety of settings to estimate systemic exposure to Neoral (measured as the area under the blood concentration curve (AUC) of the drug) in blood. We conducted a pilot study to determine whether Neoral could be administered orally immediately after heart transplantation and to determine which pharmacokinetic parameters reflect systemic drug exposure in this setting. Eight male patients (mean age 50 years) undergoing a first heart transplant were studied. Neoral was administered orally before surgery and at 12-h intervals via a nasogastric tube after surgery. Twelve-hour pharmacokinetic profiles were obtained on postoperative days 1, 3 and 5. Cyclosporine concentrations were measured with the Dade Behring Emit assay, which is specific for the parent drug. Drug concentrations were dose-normalised and drug exposure was measured by the AUC. Drug exposure following administration (AUC(0-12)) was low on day 1 but increased by 99% between postoperative day 1 and day 5 ( P<0.05), indicating more complete absorption of cyclosporine; exposure in the first 4 h post-dose (AUC(0-4)) increased by 126% ( P<0.01), reflecting more rapid cyclosporine absorption, and the maximum blood concentration observed increased by 137% ( P<0.05) during the same period. The correlation between the cyclosporine trough concentration and AUC(0-12) was low on all days. Due to the changing pattern of cyclosporine absorption, concentration measurements at a single time point could not accurately predict 12-h exposure to the drug on all study days. However, the drug concentration at 2 h post-dose had a high correlation with drug exposure during the first 4 h (correlation of C(2) to AUC(0-4): r(2)>0.93 on all days). Absorption of Neoral was low immediately after heart transplantation but improved substantially during the first 5 days after surgery. No single timed measurement of drug concentration reflected cyclosporine exposure; however, the 2-h concentration did provide an accurate measure of the early phase of drug absorption (AUC(0-4)). Oral administration of Neoral may result in inadequate immunosuppression immediately after heart transplantation unless it is supplemented either by intravenous cyclosporine or by the use of an induction agent.