Personalized tacrolimus dose requirement by CYP3A5 but not ABCB1 or ACE genotyping in both recipient and donor after pediatric liver transplantation

• Published in: PloS one 2014-10, Vol.9 (10), p.e109464-e109464
• Main Authors: Chen, Yi-kuan, Han, Long-zhi, Xue, Feng, Shen, Cong-huan, Lu, Jun, Yang, Tai-hua, Zhang, Jian-jun, Xia, Qiang
• Format: Article
• Language: English
• Subjects: Adult; ATP Binding Cassette Transporter, Sub-Family B - genetics; Child; Child, Preschool; Clinical outcomes; Cytochrome; Cytochrome P-450 CYP3A - genetics; Donors; Drug dosages; Enzymes; Female; Gene polymorphism; Genotype; Genotype & phenotype; Genotypes; Genotyping; Genotyping Techniques; Glycoproteins; Health aspects; Humans; Immunosuppressive agents; Immunosuppressive Agents - administration & dosage; Infant; Liver; Liver Transplantation; Liver transplants; Male; Medicine; Medicine and Health Sciences; Metabolism; Middle Aged; Organ transplant recipients; Patients; Pediatrics; Peptidyl-Dipeptidase A - genetics; Pharmacology; Polymorphism; Polymorphism, Single Nucleotide; Proteins; Single nucleotide polymorphisms; Single-nucleotide polymorphism; Surgery; Tacrolimus; Tacrolimus - administration & dosage; Tacrolimus - metabolism; Tissue Donors; Transplant Recipients; Transplantation; Transplants & implants; Young Adult
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0109464

Tacrolimus (TAC) is the backbone of an immunosuppressive drug used in most solid organ transplant recipients. A single nucleotide polymorphism (SNP) at position 6986G>A in CYP3A5 has been notably involved in the pharmacokinetic variability of TAC. It is hypothesized that CYP3A5 genotyping in patients may provide a guideline for TAC therapeutic regimen. To further evaluate the impact of CYP3A5 variants in donors and recipients, ABCB1 and ACE SNPs in recipients on TAC disposition, clinical and laboratory data were retrospectively reviewed from 90 pediatric patients with liver transplantation and their corresponding donors after 1 year of transplantation. The recipients with CYP3A5 *1/*1 or *1/*3 required more time to achieve TAC therapeutic range during the induction phase, and needed more upward dose during the late induction and the maintained phases, with lower C/D ratio, compared with those with CYP3A5 *3/*3. And donor CYP3A5 genotypes were found to impact on TAC trough concentrations after liver transplantation. No association between ABCB1 or ACE genotypes and TAC disposition post-transplantation was found. These results strongly suggest that CYP3A5 genotyping both in recipient and donor, not ABCB1 or ACE is necessary for establishing a personalized TAC dosage regimen in pediatric liver transplant patients.