Summary:
We retrospectively analyzed the factors that affect serum cyclosporine (CsA) concentrations up to day 14 after allogeneic hematopoietic stem cell transplantation (HSCT). In all, 103 transplant recipients who received MTX and CsA for acute GVHD prophylaxis were analyzed. No significant relationships between serum CsA concentrations and gender, age, serum creatinine levels, AST/ALT levels, or antibiotic/fluconazole administration were found by comparing median CsA concentrations or by using longitudinal or regression multivariate analyses. However, the mean of the median serum CsA concentration in patients (n=54) receiving the regimen containing cyclophosphamide (CY) (149.7 ng/ml; 95% confidence interval (CI): 132.1–167.4) was significantly (P<0.0001) lower than that in patients (n=49) receiving the non-CY regimen (217.3 ng/ml; 95% CI: 198.9–235.6). Longitudinal analysis and regression multivariate analysis showed that only administration of CY had a significant effect on the serum CsA concentration. Our results suggest that administration of CY during conditioning can reduce the effects on serum CsA concentrations during the 2 weeks following HSCT. The mechanism of this effect is not clear, but it may be due to the autoinduction of CY.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Storb R, Deeg HJ, Whitehead J et al. Methotrexate and cyclosporine compared with cyclosporine alone for prophylaxis of acute graft versus host disease after marrow transplantation for leukemia. N Engl J Med 1986; 314: 729–735.
Ruutu T, Niederwieser D, Gratwohl A, Apperley JF . A survey of the prophylaxis and treatment of acute GVHD in Europe: a report of the European Group for Blood and Marrow, Transplantation (EBMT). Chronic Leukaemia Working Party of the EBMT. Bone Marrow Transplant 1997; 19: 759–764.
Storb R, Deeg HJ, Farewell V et al. Marrow transplantation for severe aplastic anemia: methotrexate alone compared with a combination of methotrexate and cyclosporine for prevention of acute graft-versus-host disease. Blood 1986; 68: 119–125.
Seifeldin R . Drug interactions in transplantation. Clin Ther 1995; 17: 1043–1061.
Campana C, Regazzi MB, Buggia I, Molinaro M . Clinically significant drug interactions with cyclosporin. An update. Clin Pharmacokinet 1996; 30: 141–179.
Canafax DM, Graves NM, Hilligoss DM et al. Interaction between cyclosporine and fluconazole in renal allograft recipients. Transplantation 1991; 51: 1014–1018.
Kennedy MS, Yee GC, McGuire TR et al. Correlation of serum cyclosporine concentration with renal dysfunction in marrow transplant recipients. Transplantation 1985; 40: 249–253.
Yee GC, Self SG, McGuire TR et al. Serum cyclosporine concentration and risk of acute graft-versus-host disease after allogeneic marrow transplantation. N Engl J Med 1988; 319: 65–70.
Watkins PB . Drug metabolism by cytochrome P450 in the liver and small bowel. Gastroenterol Clin N Am 1992; 21: 511–524.
Nebert DW, Nelson DR, Adesnik M et al. The P450 superfamily: updated listing of all genes and recommended nomenclature for the chromosomal loci. DNA 1989; 8: 1–13.
Colvin M, Hilton J . Pharmacology of cyclophosphamide and metabolites. Cancer Treat Rep 1981; 3: 89–95.
Chang TK, Yu L, Goldstein JA, Waxman DJ . Identification of the polymorphically expressed CYP2C19 and the wild-type CYP2C9-ILE359 allele as low-Km catalysts of cyclophosphamide and ifosfamide activation. Pharmacogenetics 1997; 7: 211–221.
Chang TK, Weber GF, Crespi CL, Waxman DJ . Differential activation of cyclophosphamide and ifosphamide by cytochromes P-450 2B and 3A in human liver microsomes. Cancer Res 1993; 53: 5629–5637.
Ren S, Yang JS, Kalhorn TF, Slattery JT . Oxidation of cyclophosphamide to 4-hydroxycyclophosphamide and deschloroethylcyclophosphamide in human liver microsomes. Cancer Res 1997; 57: 4229–4235.
Roy P, Yu LJ, Crespi CL, Waxman DJ . Development of a substrate-activity based approach to identify the major human liver P-450 catalysts of cyclophosphamide and ifosfamide activation based on cDNA-expressed activities and liver microsomal P-450 profiles. Drug Metab Dispos 1999; 27: 655–666.
Connors TA, Cox PJ, Farmer PB et al. Observations on the mechanism of hydroxylation of cyclophosphamide by rat liver microsomes: the metabolism of cyclophosphamide-4-d2. Biomed Mass Spectrom 1974; 1: 130–136.
Fenselau C, Kan MN, Rao SS et al. Identification of aldophosphamide as a metabolite of cyclophosphamide in vitro and in vivo in humans. Cancer Res 1977; 37: 2538–2543.
Domeyer BE, Sladek NE . Metabolism of 4-hydroxycyclophosphamide/aldophosphamide in vitro. Biochem Pharmacol 1980; 29: 2903–2912.
Bohnenstengel F, Hofmann U, Eichelbaum M, Kroemer HK . Characterization of the cytochrome P450 involved in side-chain oxidation of cyclophosphamide in humans. Eur J Clin Pharmacol 1996; 51: 297–301.
Ruzicka JA, Ruenitz PC . Cytochrome P-450-mediated N-dechloroethylation of cyclophosphamide and ifosfamide in the rat. Drug Metab Dispos 1992; 20: 770–772.
Graham MI, Shaw IC, Souhami RL et al. Decreased plasma half-life of cyclophosphamide during repeated high-dose administration. Cancer Chemother Pharmacol 1983; 10: 192–193.
Moore MJ, Hardy RW, Thiessen JJ et al. Rapid development of enhanced clearance after high-dose cyclophosphamide. Clin Pharmacol Ther 1988; 44: 622–628.
Fasola G, Lo Greco P, Calori E et al. Pharmacokinetics of high-dose cyclophosphamide for bone marrow transplantation. Haematologica 1991; 76: 120–125.
Chang TK, Yu L, Maurel P, Waxman DJ . Enhanced cyclophosphamide and ifosfamide activation in primary human hepatocyte cultures: response to cytochrome P-450 inducers and autoinduction by oxazaphosphorines. Cancer Res 1997; 57: 1946–1954.
Hassan M, Svensson US, Ljungman P et al. A mechanism-based pharmacokinetic-enzyme model for cyclophosphamide autoinduction in breast cancer patients. Br J Clin Pharmacol 1999; 48: 669–677.
Ren S, Kalhorn TF, McDonald GB et al. Pharmacokinetics of cyclophosphamide and its metabolites in bone marrow transplantation patients. Clin Pharmacol Ther 1998; 64: 289–301.
Busse D, Busch FW, Schweizer E et al. Fractionated administration of high-dose cyclophosphamide: influence on dose-dependent changes in pharmacokinetics and metabolism. Cancer Chemother Pharmacol 1999; 43: 263–268.
Schuler U, Waidelich P, Kolb H et al. Pharmacokinetics and metabolism of cyclophosphamide administered after total body irradiation of bone marrow transplant recipients. Eur J Clin Pharmacol 1991; 40: 521–523.
Nieto Y, Xu X, Cagnoni PJ et al. Nonpredictable pharmacokinetic behavior of high-dose cyclophosphamide in combination with cisplatin and 1,3-bis(2-chloroethyl)-1-nitrosourea. Clin Cancer Res 1999; 5: 747–751.
Schuler U, Ehninger G, Wagner T . Repeated high-dose cyclophosphamide administration in bone marrow transplantation: exposure to activated metabolites. Cancer Chemother Pharmacol 1987; 20: 248–252.
Cheng TL, Passos-Coelho JL, Noe DA et al. Nonlinear pharmacokinetics of cyclophosphamide in patients with metastatic breast cancer receiving high-dose chemotherapy followed by autologous bone marrow transplantation. Cancer Res 1995; 55: 810–816.
Cheng TL, Kennedy MJ, Anderson LW et al. Nonlinear pharmacokinetics of cyclophosphamide and 4-hydroxycyclophosphamide/aldophosphamide in patients with metastatic breast cancer receiving high-dose chemotherapy followed by autologous bone marrow transplantation. Drug Metab Dispos 1997; 25: 544–551.
Gentile DM, Tomlinson ES, Maggs JL et al. Dexamethasone metabolism by human liver in vitro. Metabolite identification and inhibition of 6-hydroxylation. J Pharmacol Exp Ther 1996; 277: 105–112.
Vogt W, Welsch I . Modified TDx assay for cyclosporine and metabolites, for use with whole-blood samples. Clin Chem 1988; 34: 1459–1461.
Zucchelli GC, Pilo A, Clerico A et al. The TDx assay for cyclosporine and its metabolites in blood samples compared with HPLC and RIA methods. Drugs Exp Clin Res 1989; 15: 185–188.
Laird NM, Ware JH . Random-effects models for longitudinal data. Biometrics 1982; 38: 963–974.
Hebert MF . Contributions of hepatic and intestinal metabolism and P-glycoprotein to cyclosporine and tacrolimus oral drug delivery. Adv Drug Deliv Rev 1997; 27: 201–214.
Jones TE . The use of other drugs to allow a lower dosage of cyclosporin to be used. Therapeutic and pharmacoeconomic considerations. Clin Pharmacokinet 1997; 32: 357–367.
Yee GC, Lennon TP, Gmur DJ et al. Age-dependent cyclosporine: pharmacokinetics in marrow transplant recipients. Clin Pharmacol Ther 1986; 40: 438–443.
Yee GC, McGuire TR, Gmur DJ et al. Blood cyclosporine pharmacokinetics in patients undergoing marrow transplantation. Influence of age, obesity, and hematocrit. Transplantation 1988; 46: 399–402.
Bearman SI, Mori M, Beatty PG et al. Comparison of morbidity and mortality after marrow transplantation from HLA-genotypically identical siblings and HLA-phenotypically identical unrelated donors. Bone Marrow Transplant 1994; 13: 31–35.
Nademanee A, Schmidt GM, Parker P et al. The outcome of matched unrelated donor bone marrow transplantation in patients with hematologic malignancies using molecular typing for donor selection and graft-versus-host disease prophylaxis regimen of cyclosporine, methotrexate, and prednisone. Blood 1995; 86: 1228–1234.
Drobyski WR, Ash RC, Casper JT et al. Effect of T-cell depletion as graft-versus-host disease prophylaxis on engraftment, relapse, and disease-free survival in unrelated marrow transplantation for chronic myelogenous leukemia. Blood 1994; 83: 1980–1987.
McDonald GB, Slattery JT, Bouvier ME et al. Cyclophos-phamide metabolism, liver toxicity, and mortality following hematopoietic stem cell transplantation. Blood 2003; 101: 2043–2048.
Ferrara JL . Pathogenesis of acute graft-versus-host disease: cytokines and cellular effectors. J Hematother Stem Cell Res 2000; 9: 299–306.
Goker H, Haznedaroglu IC, Chao NJ . Acute graft-vs-host disease: pathobiology and management. Exp Hematol 2001; 29: 259–277.
Ferrara JL, Levy R, Chao NJ . Pathophysiologic mechanisms of acute graft-vs-host disease. Biol Blood Marrow Transplant 1999; 5: 347–356.
Morgan ET . Regulation of cytochromes P450 during inflammation and infection. Drug Metab Rev 1997; 29: 1129–1188.
Cheng PY, Morgan ET . Hepatic cytochrome P450 regulation in disease states. Curr Drug Metab 2001; 2: 165–183.
Clark MA, Bing BA, Gottschall PE, Williams JF . Differential effect of cytokines on the phenobarbital or 3-methylcholanthrene induction of P450 mediated monooxygenase activity in cultured rat hepatocytes. Biochem Pharmacol 1995; 49: 97–104.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Nagamura, F., Takahashi, T., Takeuchi, M. et al. Effect of cyclophosphamide on serum cyclosporine levels at the conditioning of hematopoietic stem cell transplantation. Bone Marrow Transplant 32, 1051–1058 (2003). https://doi.org/10.1038/sj.bmt.1704259
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.bmt.1704259
Keywords
This article is cited by
-
Prophylactic and therapeutic treatment of graft-versus-host disease in Japan
International Journal of Hematology (2015)
-
Pattern and associated factors of potential drug-drug interactions in both pre- and early post-hematopoietic stem cell transplantation stages at a referral center in the Middle East
Annals of Hematology (2014)
-
Prevalence of potential drug–drug interactions in bone marrow transplant patients
International Journal of Clinical Pharmacy (2011)
-
The same but different: autologous hematopoietic stem cell transplantation for patients with lymphoma and HIV infection
Bone Marrow Transplantation (2009)