Diltiazem augments the influence of MDR1 genotype status on cyclosporine concentration in Chinese patients with renal transplantation

Abstract

Aim: Co-administration of diltiazem can reduce the dosage of cyclosporine (CsA) in patients with renal transplantation. In this study, we investigated how diltiazem altered the relationship between MDR1 genetic polymorphisms and CsA concentration in Chinese patients with renal transplantation. Methods: A total of 126 renal transplant patients were enrolled. All the patients received CsA (2-4 mg·kg -1 ·d -1 ), and diltiazem (90 mg/d) was co-administered to 76 patients. MDR1-C1236T, G2677T/A, and C3435T polymorphisms were genotyped. The whole blood concentration was measured using the FPIA method, and the adjusted trough concentrations were compared among the groups with different genotypes. Results: In all patients, MDR1-C1236T did not influence the adjusted CsA trough concentration. With regard to MDR1-3435, the adjusted CsA trough concentration was significantly higher in TT carriers than in CC and CT carriers when diltiazam was co-administered (58.83±13.95 versus 46.14±7.55 and 45.18±12.35 ng/mL per mg/kg, P=0.011), and the differences were not observed in patients without diltiazam co-administered. With regard to MDR1-2677, the adjusted CsA trough concentration was significantly higher in TT carriers than in GG and GT carriers when diltiazam was co-administered (61.31±12.93 versus 52.25±7.83 and 39.70±7.26 ng/mL per mg/kg, P=0.0001). The differences were also observed in patients without diltiazam co-administered (43.27±5.95 versus 35.22±7.55 and 29.54±5.35 ng/mL per mg/kg, P=0.001). The adjusted CsA trough blood concentration was significantly higher in haplotype T-T-T and haplotype T-T-C carriers than in non-carriers, regardless of diltiazem co-administered. Conclusion: MDR1 variants influence the adjusted CsA trough concentration in Chinese patients with renal transplant, and the influence more prominent when diltiazem is co-administered.

The impact of matched and mismatched donor–recipient genotypes for MDR1 polymorphisms (G2677TA, C1236T and C3435T) on the outcomes of patients after allogeneic haematopoietic stem cell transplantation

“…Several other studies have also reported correlations between MDR1 gene polymorphisms and cyclosporine and tacrolimus concentrations. [15][16][17][18] In the present study, the incidence of grade II-IV acute GVHD and CMV viral load was higher in the MDR1 G2677TA matched group compared to the mismatched group. However, these observations did not reach statistical significance.…”

Drug–drug–gene interactions and adverse drug reactions

“…For example, cyclosporine is an ABCB1 substrate. Diltiazem (a moderate ABCB1 inhibitor [38]) has been shown to increase cyclosporin trough concentrations in Chinese patients who carry the TT genotype (low P-gp activity) at rs1045642 (C>T) in ABCB1; yet no effect was seen in other ABCB1 genotypes (e.g., CC at rs1045642) [39]. Methadone is also a P-gp substrate, acting in the brain and effluxed across the BBB via P-gp.…”

Numerical predictions of the mechanical properties of NT-ZnOw reinforced composites

“…Whisker-reinforced composites, as composite materials with structure-function integration, have excellent electric conduction and microwave absorption. Moreover, the structural load-carrying capacity of whisker-reinforced composites can be potentially applied in high-tech industry, aerospace, aviation, and other fields [3][4][5].…”