Multidrug resistance gene-1 (MDR-1) haplotypes have a minor influence on tacrolimus dose requirements.
P-glycoprotein (P-gp) and the drug metabolizing enzymes have major pharmacokinetic effects. Variability in tacrolimus absorption is influenced by P-gp activity which, in turn, is affected by single nucleotide polymorphisms (SNPs) within the multidrug resistance-1 gene (MDR-1). Tacrolimus dose requirements of 206 stable renal transplant patients were related to MDR-1 genotypes of SNPs C1236T, G2677T/A and C3435T, as well as haplotypes: C-G-C and T-T-T. Lower dose-normalized blood tacrolimus concentrations were achieved for: 2677-GG genotype patients, as compared to 2677-TT, and for 3435-CC patients as compared to 3435-TT patients. There was a small, but significant, difference in dose requirements between haplotypes C-G-C and T-T-T patients, which was not significant when patients were subclassified as producers and non-producers of cytochrome P450 3A5 (CYP3A5). The activities of CYP3A5 and P-gp have been shown to influence bioavailability of several drugs. Our data suggest that MDR-1 haplotypes have a relatively minor association with tacrolimus pharmacokinetics.
Fredericks
Salim
S
Analytical Unit, Cardiac and Vascular Sciences, St. George's-University of London, London, United Kingdom. frederic@sgul.ac.uk
Moreton
Michelle
M
Reboux
Sandrine
S
Carter
Nicholas D
ND
Goldberg
Lawrence
L
Holt
David W
DW
MacPhee
Iain A M
IA
D000293:Adolescent; D000328:Adult; D000368:Aged; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D004247:DNA / Q000097:blood / Q000235:genetics / Q000302:isolation & purification; D004305:Dose-Response Relationship, Drug; D005260:Female; D019450:Genes, MDR; D005838:Genotype; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000627:therapeutic use; D016030:Kidney Transplantation / Q000276:immunology / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D016559:Tacrolimus / Q000008:administration & dosage / Q000627:therapeutic use*
D007166:Immunosuppressive Agents; D004247:DNA; D001189:Aryl Hydrocarbon Hydroxylases; C100638:cytochrome P-450 CYP3A6 (rabbit); D016559:Tacrolimus