title: Influence of CYP3A5 polymorphism on tacrolimus maintenance doses and serum levels after renal transplantation: age dependency and pharmacological interaction with steroids.
abstract: TAC, MMF and MP are used in pediatric kidney tx. The cytochrome P450 (CYP)3A5 enzyme appears to play a role in TAC metabolism. The aims of this study were to investigate CYP3A5 polymorphism's effect on TAC dosing and the age dependency of TAC dosing by testing blood concentrations, and the interaction between steroids and TAC during the first year after tx. Genomic DNA was extracted and amplified with specific primers. CYP3A5 alleles were confirmed by direct sequencing of PCR products on an automated AB13100 capillary sequencer. We studied 48 renal transplant patients (age at tx 12±0.5yr, 22 boys) receiving TAC, MMF, MP. Of these, 79% were CYP3A5*3/*3 (non-expressers homozygotes) and 21% were CYP3A5*1/*3 (expressers). TAC trough levels were 7.1±0.4ng/mL in CYP3A5*3/*3 patients and 6.5±0.7ng/mL in CYP3A5*1/*3 group (p=0.03). CYP3A5*1/*3 patients had lower levels of dose-adjusted TAC (36.7±5.8ng/mL/mg/kg/day) to achieve target blood concentration and required higher daily dose per weight (0.21±0.03mg/kg/day) than CYP3A5*3/*3 patients, 72.4±8.0ng/mL/mg/kg/day and 0.13±0.01mg/kg/day (p<0.001). Prepubertal patients with different CYP3A5 polymorphisms required significant higher TAC doses and achieved lower dose-normalized concentration compared with pubertal patients. Both TAC dose and adjusted-dose correlated with daily MP dose in CYP3A5*1*3 (r: 0.4, p<0.03 and r: 0.4, p<0.03) and in CYP3A5*3*3 (r: 0.6, p<0.01 and r: 0.47, p<0.001) patients. CYP3A5 polymorphism performed before tx could contribute to a better individualization of TAC therapy. The higher TAC dose in prepubertal patients and the pharmacological interactions between MP and TAC may not be fully explained by different CYP3A5 polymorphisms.
authors.affiliation: Servicio de Nefrología Pediátrica, Hospital Italiano de Buenos Aires Departamento de Pediatría, Universidad de Buenos Aires. jorge.ferraris@hospitalitaliano.org.ar
authors.forename: Jorge R
authors.initials: JR
authors.lastname: Ferraris
authors.forename: Pablo F
authors.initials: PF
authors.lastname: Argibay
authors.forename: Lucas
authors.initials: L
authors.lastname: Costa
authors.forename: Graciela
authors.initials: G
authors.lastname: Jimenez
authors.forename: Paula A
authors.initials: PA
authors.lastname: Coccia
authors.forename: Lidia F R
authors.initials: LF
authors.lastname: Ghezzi
authors.forename: Verónica
authors.initials: V
authors.lastname: Ferraris
authors.forename: Waldo H
authors.initials: WH
authors.lastname: Belloso
authors.forename: María A
authors.initials: MA
authors.lastname: Redal
authors.forename: Julián M
authors.initials: JM
authors.lastname: Larriba
mesh_terms: D000293:Adolescent; D000367:Age Factors; D001835:Body Weight; D002648:Child; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D017931:DNA Primers / Q000235:genetics; D005260:Female; D006720:Homozygote; D006801:Humans; D016030:Kidney Transplantation / Q000379:methods*; D008297:Male; D008775:Methylprednisolone / Q000627:therapeutic use; D009173:Mycophenolic Acid / Q000031:analogs & derivatives / Q000627:therapeutic use; D011110:Polymorphism, Genetic; D013256:Steroids; D016559:Tacrolimus / Q000097:blood* / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D017931:DNA Primers; D013256:Steroids; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D009173:Mycophenolic Acid; D016559:Tacrolimus; D008775:Methylprednisolone