Toxicity of Cyclosporine Metabolites

Copeland, Kenneth R.; Thliveris, James A.; Yatscoff, Randall W.

doi:10.1097/00007691-199011000-00003

Cited by 40 publications

(16 citation statements)

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“…It is important to note that these gene polymorphisms may influence systemic CNI exposure, but because therapeutic drug monitoring leads to targeted CNI serum concentrations, the additional effects of these gene polymorphisms on CNI nephrotoxicity appear to be at the level of intrarenal metabolism, and hence local rather than systemic exposure to CNIs and their metabolites (Copeland et al 1990;el-Agroudy et al 2004;El-Dahshan et al 2006;Roby and Shaw 1993).…”

Section: The Search For Individualized Transplant Medicinementioning

confidence: 99%

The genetics of kidney transplantation

Pallet

Thervet

2011

Hum Genet

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Over the last decade, the search for gene variants with the potential to influence transplant outcomes or predispose individuals to host-recipient-related phenotypes has generated a considerable number of studies with conflicting results. Thousands of genotypes have been associated with complex traits related to transplant medicine, including acute rejection, immunosuppressive drug metabolism and side effects, infections, long-term outcomes, and cardiovascular complications. However, these efforts have given disappointing results, both in terms of gaining understanding of the biological basis of disease and in patient management. The methodological weaknesses that constitute the major limitations of most of these studies have been discussed widely. A new generation of approaches is needed to understand the relationship between gene variants and complex kidney transplantation traits. These approaches should be global, to generate original pathophysiological hypotheses, and should rely on advanced genomic tools, including Genome Wide Association studies and Whole Genome Sequencing technologies. Such enterprises will only be successful with the creation of international consortiums that connect partners in clinical, industrial, and academic transplant medicine.

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Section: The Search For Individualized Transplant Medicinementioning

confidence: 99%

The genetics of kidney transplantation

Pallet

Thervet

2011

Hum Genet

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“…As mentioned in the introduction, it remains unclear if elevated levels of AM4N contribute to nephrotoxicity or if they have useful immunosuppressive activity, because these findings are mainly based on in vitro experiments (Radeke et al, 1992). In cell culture, AM4N showed changes consistent with vacuolization seen in tubular cells exposed to CsA in vivo, whereas other CM that circulate in higher concentrations (e.g., AM1) did not cause such damages (Copeland et al, 1990). Although extrapolation to humans is not possible at this time, our data in rats suggest the need of further investigation.…”

Section: Discussionmentioning

confidence: 99%

Comparison of Bioavailability and Metabolism with Two Commercial Formulations of Cyclosporine A in Rats

Koehler

Kuehnel²,

Kees³

et al. 2002

Drug Metab Dispos

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“…CSA is extensively metabolized by the liver microsomal P-450IIIA oxydase system (Cheung et al, 1988a;Maurer, 1985), and a series of metabolites have been identified and structurally characterized (Maurer et al, 1984). The major metabolites of CSA have been purified from bile of transplant patients (Cheung et al, 1988b), and most of them lack the immunosuppressant activity (Yatscoff et al, 1991) and toxicity (Copeland et al, 1990) of CSA when tested in vitro. CSA is an effective inhibitor of P-gp and of another member of the ATP-binding cassette family of membrane transporters, the MDR-associated protein (MRP) (Leier et al, 1994).…”

Section: Discussionmentioning

confidence: 99%

Reversal activity of cyclosporin A and its metabolites M1, M17 and M21 in multidrug-resistant cells

et al. 1997

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Cyclosporin A (CSA) is an effective inhibitor of the P-glycoprotein (P-gp) activity and has been shown to modulate multidrug resistance (MDR) in in vitro experimental models. During degradation of CSA, the metabolites arising from the parental compound reach high levels in the serum of patients, and it is not clear whether these metabolites maintain the reversal activity of the parental compound, like the metabolites of verapamil. In an in vitro experimental model, we compared the reversal activity of CSA and 3 CSA metabolites (M1, M17, and M21) in the range of concentrations obtained in whole blood during a clinical trial with CSA used as a revertant agent. As experimental model we used LoVo-resistant cells. Our in vitro studies indicated that the metabolic hydroxylation and demethylation of CSA lead to molecules that greatly differ from the parent drug in their reversal activity. In the range of concentration detected in the whole blood of the patients (1-3 microM), CSA had a significant reversal activity. It decreased the IC50 of antineoplastic drugs involved in MDR (vincristine, taxol, doxorubicin and etoposide) but not the IC50 of platinum or methotrexate. CSA increased intracellular doxorubicin content and inhibited P-gp 3[H]azidopine photolabeling. Conversely, CSA metabolite concentrations superimposable to those observed in the patients (0.5-2.2 microM) had no sensitizing effects on the cytotoxicity of MDR-related anti-neoplastic drugs, nor did they affect 3[H]azidopine photolabeling or doxorubicin uptake. This study demonstrates that, during degradation of CSA, metabolite derivatives arise that have a very different reversal activity from that of the parental compound.

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Toxicity of Cyclosporine Metabolites

Cited by 40 publications

References 0 publications

The genetics of kidney transplantation

The genetics of kidney transplantation

Comparison of Bioavailability and Metabolism with Two Commercial Formulations of Cyclosporine A in Rats

Reversal activity of cyclosporin A and its metabolites M1, M17 and M21 in multidrug-resistant cells

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