P.1.e.006 Regional increase in P-glycoprotein function in the blood-brain-barrier of patients with chronic schizophrenia

Abstract

The main genes involved in the pharmacokinetics of immunosuppressive drugs are those encoding cytochrome P450 (CYP) family enzymes and multidrug resistance 1 (ABCB1). In this study, 87 Italian teenagers with transplanted kidneys (mean age 11.6 ± 4.8 years) receiving calcineurin inhibitors (CNIs) were genotyped for the single nucleotide polymorphisms (SNPs) CYP3A5*1/3 and CYP3A4*1B for CYP3A, and C1236T, G2677T/A, C3435T and IVS21+49 for ABCB1, and retrospectively evaluated for the influence of the screened SNPs on CNI blood level at different post-transplantation times. The CYP3A5*1 allele was present in 7% of the patients, and the CYP3A4*1B allele was present in 3% of patients. The ABCBl C1236T, G2677T/A and C3435T SNPs C, G and T occurred frequently (55%, 53% and 54%, respectively). The frequency of the T allele of IVS21+49 was 86%. The frequency of SNPs in both genes was comparable with that reported in other European Caucasian populations but different from that found in Asians or Afro-Americans. None of the cyclosporine (CsA) pharmacokinetic parameters were associated with the CYP3A5 genetic polymorphism, whereas the presence of the A allele in some patients was responsible for the required administration of a significantly increased dose of tacrolimus (Tac) that was necessary to reach therapeutic target levels. None of the Tac pharmacokinetic parameters were associated with ABCB1 SNPs, but ABC1 SNPs had early effects on the CsA exposure index and dose requirements. In conclusion, because SNPs of the CYP3A and ABCB1 genes may be associated with CNI pharmacokinetic parameters and exposure indices, pre-transplant genetic screening should be considered in order to avoid immunosuppressant-related adverse events.