From gut to kidney: Transporting and metabolizing calcineurin-inhibitors in solid organ transplantation

Knops, Noël; Levtchenko, Elena; Heuvel, Bert van den; Kuypers, Dirk

doi:10.1016/j.ijpharm.2013.05.033

Cited by 63 publications

(100 citation statements)

References 272 publications

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“…However, a large concentration variation of these drugs in the plasma of these individuals is assigned to inter-individual differences in drug absorption and metabolism mainly due to gene polymorphism of metabolic pathways of immunosuppressive drugs (Knops et al, 2013;Cusinato et al, 2014). The time of transplantation also interferes with plasma concentrations because, soon after the transplant, the patients usually require higher dosages of immunosuppressive drugs to guarantee graft maintenance (induction treatment).…”

Section: Discussionmentioning

confidence: 99%

“…A complex and often interdependent set of factors appears relevant in determining drug exposure. These include recipient characteristics such as age, race, body composition, organ function, and food intake, but also graft-related characteristics such as: size, donor-age, and time after transplantation (Knops et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

“…These drugs are commonly co-administered with an antiproliferative agent, such as mycophenolate mofetil, sirolimus or azathioprine with or without corticosteroids, and it has caused a modest improvement in outcome (Gaston, 2006;Knops et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Cytotoxic and genotoxic effects of high concentrations of the immunosuppressive drugs cyclosporine and tacrolimus in MRC-5 cells

Cilião

Ribeiro

Camargo-Godoy

et al. 2015

Experimental and Toxicologic Pathology

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Cytotoxic and genotoxic effects of high concentrations of the immunosuppressive drugs cyclosporine and tacrolimus in MRC-5 cells

Cilião

Ribeiro

Camargo-Godoy

et al. 2015

Experimental and Toxicologic Pathology

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“…4 In particular, the carriers of a sequence variant in intron 3 of the CYP3A5 gene, designated CYP3A5*1, demonstrated to have up to two-fold higher tacrolimus dose requirements versus homozygous CYP3A5*3 carriers. 5 This allele is dominant in people of African descent (allele frequency: 70−90%) but is also present in 5−20% of Caucasians.…”

Section: ■ Introductionmentioning

confidence: 99%

The Functional Implications of Common Genetic Variation in CYP3A5 and ABCB1 in Human Proximal Tubule Cells

et al. 2015

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Biopsy-derived and immortalized human PTC cell lines demonstrate functional expression of genes involved in CNI metabolism. Differences in functional expression were detected according to common genetic variants in CYP3A5 and ABCB1. The studied genetic variants had a significant impact on in vitro tacrolimus metabolism. In particular, ciPTC with the combined CYP3A5*1/ABCB1 3435TT genotype demonstrated higher tacrolimus disappearance versus ciPTCs with a different pharmacogenetic profile. This in vitro model stresses the importance of the incorporation of pharmacogenetic variation in studies involved in (renal) drug disposition.

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“…1 Since their introduction in 1980, the calcineurin inhibitors (CNIs) cyclosporine and tacrolimus have been highly regarded, as evidenced by the significantly better outcomes notable with these agents, that is, more than 90% 1-year graft survival while maintaining an acute rejection rate of less than 20%. 2 However, the excellent results of short-term allograft survival have not translated into long-term graft survival. Longterm survival continues to show a slow, steady decline with some categories falling below 50% over 10 years.…”

Section: Introductionmentioning

confidence: 99%

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Jayant

Bridson

Sharma³

et al. 2017

Exp Clin Transplant

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Objectives: This review focuses on the current limited evidence of graft function and graft survival in various immunosuppressive regimens involving mammalian target of rapamycin inhibitors with or without calcineurin inhibitors. Materials and Methods: We evaluated the current literature for describing the role of mammalian target of rapamycin inhibitors as an alternative to calcineurin inhibitors by searching the PubMed, EMBASE, Cochrane, Crossref, and Scopus databases using medical subject heading terms. Results: Our detailed analyses of all relevant literature showed use of mammalian target of rapamycin inhibitor-based de novo regimens, early calcineurin inhibitor withdrawal with subsequent introduction of mammalian target of rapamycin inhibitor-based regimens, and late conversion from a calcineurin inhibitor-based regimen to mammalian target of rapamycin inhibitor-based regimens. Notably, early calcineurin inhibitor withdrawal with subsequent introduction of mammalian target of rapamycin inhibitor-based regimen seemed to be a more practical and realistic approach toward immunosuppressive treatment of renal transplant recipients. However, in view of the high rejection rate observed in these studies, it is advisable not to offer these regimens to patients with moderate to high immunologic risk. Conclusions: The present evidences suggest that treatment with mammalian target of rapamycin inhibitors allows early and substantial calcineurin inhibitor minimization. The mammalian target of rapamycin inhibitors everolimus and sirolimus are preferred due to their complementary mechanisms of action and favorable nephrotoxicity profile, which have opened the way for calcineurin inhibitor reduction/withdrawal in the early posttransplant period.

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From gut to kidney: Transporting and metabolizing calcineurin-inhibitors in solid organ transplantation

Cited by 63 publications

References 272 publications

Cytotoxic and genotoxic effects of high concentrations of the immunosuppressive drugs cyclosporine and tacrolimus in MRC-5 cells

Cytotoxic and genotoxic effects of high concentrations of the immunosuppressive drugs cyclosporine and tacrolimus in MRC-5 cells

The Functional Implications of Common Genetic Variation in CYP3A5 and ABCB1 in Human Proximal Tubule Cells

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