BACKGROUNDS: Sirolimus (SRL) absorption and metabolism are affected by p-glycoprotein-mediated transport and CYP3A enzyme activity, which are further under the influences of cytokine concentrations. This retrospective study determined the associations of adenosine triphosphate-binding cassette, subfamily B, member 1 (ABCB1) 1236C>T, 2677 G>T/A, and 3435C>T, cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) -392A>G, cytochrome P450, family 3, subfamily A, polypeptide 5 (CYP3A5) 6986A>G and 14690G>A, interleukin (IL)-10 -1082G>A, and tumor necrosis factor (TNF) -308G>A polymorphisms with SRL dose-adjusted, weight-normalized trough concentrations (C/D) at 7 days, and at 1, 3, 6, and 12 months after initiation of SRL. METHODS: Genotypes for 86 renal transplant patients who received SRL-based maintenance immunosuppressive therapy were determined using polymerase chain reaction followed by chip-based mass spectrometry. The changes of log-transformed C/D over the days posttransplantation were analyzed using a linear mixed-effects model, with adjustments for body mass index and weight-normalized doses of tacrolimus, prednisone, clotrimazole, and statins. RESULTS: ABCB1 3435C>T and IL-10 -1082G>A were significantly associated with log C/D (P=0.0016 and 0.0394, respectively). Mean SRL C/D was 48% higher in patients with ABCB1 3435CT/TT genotype than those with 3435CC genotype, and was 24% higher in IL-10 -1082GG compared with -1082AG/AA. CONCLUSIONS: ABCB1 3435C>T and IL-10 -1082G>A were significantly associated with long-term SRL dose requirements. Genetics can play a significant role in SRL dosing and may be useful in therapeutic monitoring of SRL in renal transplantation. Future replication studies are needed to confirm these associations.
BACKGROUNDS: Sirolimus (SRL) absorption and metabolism are affected by p-glycoprotein-mediated transport and CYP3A enzyme activity, which are further under the influences of cytokine concentrations. This retrospective study determined the associations of adenosine triphosphate-binding cassette, subfamily B, member 1 (ABCB1) 1236C>T, 2677 G>T/A, and 3435C>T, cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) -392A>G, cytochrome P450, family 3, subfamily A, polypeptide 5 (CYP3A5) 6986A>G and 14690G>A, interleukin (IL)-10 -1082G>A, and tumor necrosis factor (TNF) -308G>A polymorphisms with SRL dose-adjusted, weight-normalized trough concentrations (C/D) at 7 days, and at 1, 3, 6, and 12 months after initiation of SRL. METHODS: Genotypes for 86 renal transplant patients who received SRL-based maintenance immunosuppressive therapy were determined using polymerase chain reaction followed by chip-based mass spectrometry. The changes of log-transformed C/D over the days posttransplantation were analyzed using a linear mixed-effects model, with adjustments for body mass index and weight-normalized doses of tacrolimus, prednisone, clotrimazole, and statins. RESULTS:ABCB1 3435C>T and IL-10 -1082G>A were significantly associated with log C/D (P=0.0016 and 0.0394, respectively). Mean SRL C/D was 48% higher in patients with ABCB1 3435CT/TT genotype than those with 3435CC genotype, and was 24% higher in IL-10 -1082GG compared with -1082AG/AA. CONCLUSIONS:ABCB1 3435C>T and IL-10 -1082G>A were significantly associated with long-term SRL dose requirements. Genetics can play a significant role in SRL dosing and may be useful in therapeutic monitoring of SRL in renal transplantation. Future replication studies are needed to confirm these associations.
Authors: P Kuehl; J Zhang; Y Lin; J Lamba; M Assem; J Schuetz; P B Watkins; A Daly; S A Wrighton; S D Hall; P Maurel; M Relling; C Brimer; K Yasuda; R Venkataramanan; S Strom; K Thummel; M S Boguski; E Schuetz Journal: Nat Genet Date: 2001-04 Impact factor: 38.330
Authors: S John Swanson; Douglas A Hale; Roslyn B Mannon; David E Kleiner; Linda C Cendales; Christine E Chamberlain; Shirley M Polly; David M Harlan; Allan D Kirk Journal: Lancet Date: 2002-11-23 Impact factor: 79.321
Authors: B D Kahan; K L Napoli; P A Kelly; J Podbielski; I Hussein; D L Urbauer; S H Katz; C T Van Buren Journal: Clin Transplant Date: 2000-04 Impact factor: 2.863
Authors: E G Schuetz; D R Umbenhauer; K Yasuda; C Brimer; L Nguyen; M V Relling; J D Schuetz; A H Schinkel Journal: Mol Pharmacol Date: 2000-01 Impact factor: 4.436
Authors: S Hoffmeyer; O Burk; O von Richter; H P Arnold; J Brockmöller; A Johne; I Cascorbi; T Gerloff; I Roots; M Eichelbaum; U Brinkmann Journal: Proc Natl Acad Sci U S A Date: 2000-03-28 Impact factor: 11.205
Authors: Wai-Johnn Sam; Christine E Chamberlain; Su-Jun Lee; Joyce A Goldstein; Douglas A Hale; Roslyn B Mannon; Allan D Kirk; Yuen Yi Hon Journal: Transplantation Date: 2012-11-15 Impact factor: 4.939