Interaction Of Cyclosporin Research Articles

Renal Transplant Obstruction by B Cell Lymphoproliferative Disorder: Case Report and Review of the Literature

We report a case of renal transplant ureteral obstruction caused by a cyclosporine-associated B cell lymphoproliferative disorder. The interaction of cyclosporine with Epstein-Barr virus infections and the predisposition towards B cell lymphoproliferative disorders are reviewed. The characterization of these tumors by deoxyribonucleic acid hybridization studies and a review of the clinical experience treating these disorders also are presented.

Interactions of cyclosporine with renal proximal tubule cells and cellular membranes.

Cyclosporine-induced nephrotoxicity is a limiting factor in the clinical use of cyclosporine. Since the manner in which cyclosporine interacts with proximal tubule cells and their membranes may provide insight into the cellular pathophysiology of cyclosporine toxicity, experiments were undertaken to characterize the interactions of cyclosporine with proximal tubule cells, renal brush border membranes, and renal cortical mitochondria. Cyclosporine bound to isolated rat renal brush border membranes in a saturable manner with a Kd of 0.38 microM and an nmax of 0.33 nmoles/mg protein. Scatchard analysis suggested that the interaction of cyclosporine at low concentrations with brush border membranes was consistent with a partitioning process rather than binding to a specific membrane component. Cyclosporine inhibited rat renal cortical mitochondrial respiration in a dose-dependent manner, with 8 microM as a threshold dose. This inhibitory effect was greater for respiration supported by succinate than pyruvate-malate. TMPD-ascorbate-supported respiration was unaffected. Suspensions of rabbit renal proximal tubule segments were incubated in vitro with 0.5-500 microM 3H-cyclosporine to measure the kinetics of cyclosporine uptake. Uptake was rapid (80% after 10 min) and saturable at 100 microM, with 9 nmoles cyclosporine/mg protein accumulated. Incubation of suspensions of enriched in rabbit renal proximal tubule segments with 10 microM cyclosporine in vitro for 2 hr with or without 22.5 min of hypoxia, or for 16 hr without hypoxia, had no effect on a variety of quantitative metabolic parameters of cell injury, including basal and uncoupled tubule respiratory rates and tubule K+, Ca++ and adenine nucleotide levels. These results demonstrate that cyclosporine interacts with critical renal membrane components at low concentrations but this interaction does not result in proximal renal tubular cell injury acutely in vitro.

Interaction of cyclosporin A with 1,2-dimyristoyl- sn-glycero-3-phosphocholine unilamellar vesicles studied by electron spin resonance

Thermally induced changes of unilamellar 1,2-dimyristoyl- sn-glycero-3-phosphocholine (DMPC) liposomes and DMPC liposomes containing cyclosporin A (CsA) were studied by electron spin resonance (ESR) spectroscopy with 5-, 12-, or 16-nitroxide stearic acid (NO-SA) as probes. All liposomes were purified by Sepharose 4B column chromatography and the amount of CsA associated with these liposomes was determined. The results obtained established that the temperature range of the gel-to-liquid crystalline phase transition of liposomes does not broaden significantly in the presence of CsA. In addition, the order of parameters of these liposomes obtained with 5-NO-SA as a probe showed no significant influence of CsA. It was concluded that CsA does not interact with the hydrocarbon region of DMPC liposomes but resides exclusively within the aqueous compartment of liposomes.

Cyclosporine metabolism in human liver: identification of a cytochrome P-450III gene family as the major cyclosporine-metabolizing enzyme explains interactions of cyclosporine with other drugs.

The rate of formation of the three initial metabolites of cyclosporine metabolism has been determined in liver microsomes of 15 kidney transplant donors. Interindividual variation in metabolite formation was considerable but all three metabolites varied in parallel. An antiserum raised against a steroid-inducible rat cytochrome P-450 (P-450 PCN) strongly inhibited the formation of these metabolites. Immunoquantitation of the protein recognized by a monoclonal antibody reacting with human cytochromes P-450 of the P-450III gene family, homologues of rat P-450 PCN and rabbit P-4503C, revealed a high degree of correlation with microsomal cyclosporine metabolism. The data suggest that this cytochrome P-450 is the major cyclosporine-metabolizing enzyme in human liver. The substrate specificity and the known inducers and inhibitors of this cytochrome P-450 explain several clinically observed drug interactions with cyclosporine.

Adverse reactions and interactions of cyclosporin.

Cyclosporin is a potent, widely used specific immunosuppressive agent which affects T-helper cells, and has little myelotoxicity. Its pharmacokinetics are complex and many of its actions remain poorly understood. Numerous side effects have been reported, affecting most organs. Most troublesome have been renal injury, systemic hypertension and vascular changes. Oral use is more effective than intramuscular and safer than the intravenous route. Interactions with other drugs include those which affect hepatic metabolism and those which reduce clearance. Aminoglycosides, macrolide antibiotics, imidazole derivatives, calcium channel blockers, sulphonamides and steroids are included in such interactions. Other metabolic effects of cyclosporin are more subtle and include hyperchloraemic alkalosis, changes in serum potassium and magnesium and effects on testosterone and prolactin levels. Acute poisoning with cyclosporin has been reported, again without myelosuppression. Cyclosporin is an important agent with multisystem toxicity, which requires precise monitoring of drug concentrations, liver and renal function, haemoglobin levels and plasma electrolytes. Cyclosporin pharmacodynamics and interactions with other drugs need to be carefully considered if lower rates of toxicity are to be achieved.

Antibiotics see Cyclosporin interaction

Antibiotics see Cyclosporin interaction

Nicardipine interaction see Cyclosporin interaction

Nicardipine interaction see Cyclosporin interaction

Androgen interaction see Cyclosporin interaction

Androgen interaction see Cyclosporin interaction

Cyclosporin interaction see Rifampicin interaction

Cyclosporin interaction see Rifampicin interaction