A drug transporter for all ages? ABCB1 and the developmental pharmacogenetics of cyclosporine.
Evaluation of: Fanta S, Niemi M, Jönsson S et al.: Pharmacogenetics of cyclosporine in children suggests an age-dependent influence of ABCB1polymorphisms. Pharmacogenet. Genomics 18(2), 77-90 (2008). The clinical use of the immunosuppressive agent cyclosporine is complicated by its toxicity, narrow therapeutic window and highly variable pharmacokinetics between individuals. In adults, genetic polymorphisms in the genes encoding the cyclosporine-metabolizing enzymes CYP3A4 and CYP3A5, as well as the ABCB1 gene, which encodes the efflux-pump P-glycoprotein, seem to have a limited effect, if any, on cyclosporine pharmacokinetics. However, the authors have now reported for the first time an association between cyclosporine oral bioavailability and the ABCB1 c.1236C>T and c.2677G>T polymorphisms, as well as the related haplotype c.1199G-c.1236C-c.2677G-c.3435C, in children with end-stage renal disease older than 8 years of age. Carriers of the variant alleles had a cyclosporine oral bioavailability that was around 1.5-times higher compared with noncarriers. This association was not observed in children younger than 8 years of age. In addition, no relation between cyclosporine disposition and genetic variation in the CYP3A4, CYP3A5, ABCC2, SLCO1B1 and NR1I2 genes was observed. These data suggest that the effect of ABCB1 polymorphisms on cyclosporine pharmacokinetics is related to age, and thus developmental stage. Although further study is necessary to establish the predictive value of ABCB1 genotyping for individualization of cyclosporine therapy in children older than 8 years, an important step towards further personalized immunosuppressive drug therapy has been made.
Hesselink
Dennis A
DA
Erasmus MC, Department of Internal Medicine, Division of Nephrology and Renal Transplantation, PO Box 2040, 3000 CA Rotterdam, The Netherlands. d.a.hesselink@erasmusmc.nl
van Schaik
Ron H N
RH
Nauta
Jeroen
J
van Gelder
Teun
T
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000328:Adult; D000375:Aging / Q000235:genetics; D002648:Child; D016572:Cyclosporine / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008658:Inactivation, Metabolic / Q000235:genetics; D016030:Kidney Transplantation; D000089762:Multidrug Resistance-Associated Protein 2; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide
C513055:ABCB1 protein, human; C000715087:ABCC2 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D007166:Immunosuppressive Agents; D000089762:Multidrug Resistance-Associated Protein 2; D016572:Cyclosporine