RÉSUMÉ
BACKGROUND: Individual differences in the pharmacokinetics (PK) of tacrolimus (TAC), an immunosuppressive drug, are reportedly associated with single-nucleotide polymorphisms (SNPs) of cytochrome P450 (CYP) 3A5 and multidrug resistance protein 1 (MDR1). We determined the effect of SNPs in CYP3A5 and MDR1 exons 21 and 26 on TAC PK parameters. METHODS: Thirty-eight Japanese patients who underwent renal transplantation were genotyped for CYP3A5 and exons 21 and 26 of MDR1 with the use of polymerase chain reaction-restriction fragment length polymorphism analysis. TAC concentrations were determined 3 weeks after renal transplantation and PK parameters calculated. RESULTS: The area under the blood concentration-time curve (AUC) in CYP3A5 expressers was significantly higher than that in CYP3A5 nonexpressers (CYP3A5*3/*3). Patients with the MDR1 exon 21 A allele (G2677A) showed higher dose-adjusted AUC (AUC/D) and lower doses of TAC than those who did not possess that allele. Furthermore, patients with both CYP3A5*3/*3 and MDR1 G2677A showed significantly lower TAC doses and higher dose-adjusted trough levels (C/D) and AUC/D than those without those genotypes. There was no significant association between MDR1 exon 26 polymorphism and the PK of TAC. CONCLUSIONS: Patients with both CYP3A5*3/*3 and MDR1 G2677A had higher blood TAC concentrations than those without those genotypes. Japanese patients should be carefully monitored for consideration of lower TAC doses, because 24% of Japanese patients have double mutations.
Sujet(s)
Cytochrome P-450 CYP3A/génétique , Immunosuppresseurs/pharmacocinétique , Polymorphisme de nucléotide simple , Tacrolimus/pharmacocinétique , Sous-famille B de transporteurs à cassette liant l'ATP/génétique , Adulte , Allèles , Asiatiques/génétique , Exons , Femelle , Génotype , Humains , Transplantation rénale , Mâle , Adulte d'âge moyen , Mutation , Variants pharmacogénomiques , Réaction de polymérisation en chaîneRÉSUMÉ
Eight-week-old male Crj:Donryu rats underwent subtotal resection of the fundus and X-ray irradiation. Six months later the animals were autopsied and examined for intestinal metaplasia. The numbers of alkaline phosphatase-positive foci with the two treatments in combination were significantly increased, compared to the operation alone and non-treatment groups. Histologically assessed intestinal metaplasia was also increased in the combined treatment group. In conclusion, subtotal resection of the fundus combined with X-ray irradiation is an effective induction protocol for intestinal metaplasia.
