Cyclosporin metabolism

Cyclosporine is an immunomodulating agent used mainly to inhibit rejection after transplantations and it has a narrow therapeutic interval. Grapefruit juice is a strong inhibitor of the cyclosporine metabolism (CYP 3A4) and increases the blood concentration of cyclosporine. This can lead to toxicity but can also be used to reduce the doses and decrease the costs of the cyclosporine treatment. 

Ahmed, S.S., Napoli, K.L. and Strobel, H. W. (1995) Oxygen radical formation during cytochrome P450-catalyzed cyclosporine metabolism in rat and human liver microsomes at varying hydrogen ion concentrations. Molecular and Cellular Biochemistry, 151 (2),... 

Kolars JC, Stetson PL, Rush BD, Ruwart MJ, Schmiedlin-Ren P and Duell EA (1992) Cyclosporin Metabolism by P450IIIA in Rat Enterocytes. Transplantation 53 pp 596-602. 

While calcium antagonists can be effective agents in treating cyclosporine-associated hypertension, use care because interference with cyclosporine metabolism may require a dosage adjustment. 

Kronbach T, Fischer V, Meyer UA. Cyclosporine metabolism in human liver identification of a cytochrome P450III gene family as the major cyclosporine metabolizing enzyme explains interactions of cyclosporine with other drugs. Clin Pharmacol Ther 1988 43 630-635. 

Cyclosporine [P] Decreased cyclosporine metabolism with diltiazem, nicardipine, verapamil. 

Variable effect on renal function and cyclosporine metabolism. Monitor cyclosporine levels and renal function carefully... 

Christians U, Sewing KF. 1993. Cyclosporin metabolism in transplant patients. Pharmacol Then 57 291-345. 

Wang H, Faucette S, Moore R et al. (2004) Human constitutive androstane receptor mediates induction of CYP2B6 gene expression by phenytoin. J Biol Chem 279 29295-29301 Watkins PB (1990) The role of cytochromes P-450 in cyclosporine metabolism. J Am Acad Dermatol 23 1301-1309... 

Lampen A, Christians U, Bader A, Hackbarth I, Sewing KF. Drug interactions and interindividual variability of cyclosporin metabolism in the small intestine. Pharmacology 1996 52 159-68. 

S. S. Ahmed, K. L. Napoli, H. W. Strobel, Oxygen Radical Formation During Cytochrome P450-Catalyzed Cyclosporine Metabolism in Rat and Human Liver Microsomes at Varying Hydrogen Ion Concentrations, Mol Cell Biochem 151 (1995) 131-40. 

Cyclosporine is biotransformed primarily in the liver by CYP3A4 however, alternate metabolic pathways may yield toxic metabolites. Most of the cyclosporin dose is excreted in bile as an active metabolite. Less than 1% is excreted as unchanged drug. Inducers of CYP3A increase cyclosporine metabolism, whereas competitors may increase cyclosporine to potentially toxic levels. 

The interaction between ketoconazole and cyclosporine has been exploited in order to reduce drug costs associated with administration of cyclosporine following organ transplantation. Relative to ketoconazole and itraconazole, fluconazole appears to be intermediate in its ability to inhibit human cytochromes P450. The magnitude of fluconazole-induced inhibition of cyclosporine metabolism appears, however, to depend on the dosage of fluconazole. 

Marked increases in plasma cyclosporine following erythromycin in several cases and healthy subjects probably due to inhibition of cyclosporine metabolism. 

Cooney GF, Mochon M, Kaiser B, Dunn SP, Gold ith B. Effects of carbamazepine on cyclosporine metabolism in pediatric renal transplant recipients. Pharmacotherapy (1995) 15, 353-6. 

Sorenson AL, Lovdahl M, Hewitt JM, Granger DK, Almond PS, Russlie HQ, Barber D, Matas AJ, Canafax DM Effects of ketoconazole on cyclosporine metabolism in renal allograft recipients. TransplantProc( 994) 26, 2822. 

Toupance O, Lavaud S, Canivet E, Bemaud C, Hotton J-M, Chanard J. Antihypertensive effect of amlodipine and lack of interference with cyclosporine metabolism in renal transplant recipients. Hypertension (1994) 24, 297-300. 

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