CYP3A5 Gene Variation Influences Cyclosporine A Metabolite Formation and Renal Cyclosporine Disposition

Abstract

Background Higher concentrations of AM19 and AM1c9, secondary metabolites of cyclosporine A (CsA), have been associated with nephrotoxicity in organ transplant patients. The risk of renal toxicity may depend upon the accumulation of CsA and its metabolites in the renal tissue. We evaluated the hypothesis that CYP3A5 genotype, and inferred enzyme expression, affects systemic CsA metabolite exposure and intra-renal CsA accumulation. Methods An oral dose of CsA was administered to 24 healthy volunteers who were selected based on their CYP3A5 genotype. CsA and its six main metabolites in whole blood and urine were measured by LC-MS. In vitro incubations of CsA, AM1, AM9 and AM1c with recombinant CYP3A4 and CYP3A5 were performed to evaluate the formation pathways of AM19 and AM1c9. Results The mean CsA oral clearance was similar between CYP3A5 expressors and nonexpressors. However, compared to CYP3A5 nonexpressors, the average blood AUC for AM19 and AM1c9 was 47.4% and 51.3% higher in CYP3A5 expressors (P = 0.040 and 0.011, respectively), corresponding to 30% higher AUCmetabolite/AUCCsA ratios for AM19 and AM1c9 in CYP3A5 expressors. The mean apparent urinary CsA clearance, based on a 48-hour collection, was 20.4% lower in CYP3A5 expressors compared to CYP3A5 nonexpressors (4.2 ± 1.0 and 5.3 ± 1.3 mL/min, respectively, P = 0.037), which is suggestive of CYP3A5-dependent intra-renal CsA metabolism. Conclusions At steady-state, intra-renal accumulation of CsA and its secondary metabolites should depend on the CYP3A5 genotype of the liver and kidneys. This may contribute to inter-patient variability in the risk of CsA-induced nephrotoxicity.

A systematic review of acute kidney injury in pediatric allogeneic hematopoietic stem cell recipients

“…This was reported as a risk factor for AKI in two studies, where AKI was rapidly reversible with dose reduction . Cyclosporine is the mainstay of GVHD prophylaxis in HSCT but has a relatively narrow therapeutic range, there may be considerable interpatient variability in drug metabolism , and the optimal method of therapeutic monitoring is unclear. The usual monitoring of serum levels using trough concentration is useful as low levels are predictive of GVHD ; however, trough levels correlate poorly with total exposure and reliance on them may increase the risk of nephrotoxicity .…”

Role of pharmacogenomics in dialysis and transplantation

“…Notably, blood levels may not reflect local accumulation of calcineurin inhibitors in renal tissue and risk of nephrotoxicity. For example, Zheng et al showed that in healthy volunteer CYP3A5 expressers and nonexpressers, cyclosporine oral clearance was similar, but CYP3A5 expressers had 50% higher area under the concentration time curves of active cyclosporine metabolites, with decreased urinary clearance, suggesting increased intra-renal accumulation that could contribute to nephrotoxicity (50). Another study of cyclosporine treated kidney transplant recipients showed that even though cyclosporine blood levels were not associated with ABCB1 polymorphisms, those homozygous for 3435TT had an increased odds of nephrotoxicity (OR 4.2, 95% CI 1.3–13.9) and gingival hyperplasia, again suggesting blood levels may not fully reflect exposure at target sites (51).…”

Neurovascular Unit in Chronic Pain

“…Coadministration of cyclosporine A (P-gp inhibitor) with morphine in rats increased morphine transport through the BBB in a dose-dependent manner [26]. In the clinical practice, reducing tolerance to morphine by co-administration with cyclosporine A is unfeasible due to severe side effects (nephro- and neurotoxicity) [105, 106]. …”