Abstract
Cyclosporin (CsA) is currently the main immunosuppressive agent used in organ transplantation with considerable improvement in graft survival. Oral CsA solution is highly lipophilic, and its bioavailability may be reduced in cystic fibrosis (CF) heart-lung transplant recipients with pancreatic, gastrointestinal, and hepatic insufficiency. The bioavailability of oral CsA solution in 7 CF transplant recipients (5 male and 2 female with a mean age of 27 years and a mean weight of 49 kg) and 3 non-CF heart-lung recipients (1 male and 2 female with a mean age of 41 years and a mean weight of 60 kg) was studied.
Following intravenous CsA administration, the kinetic curves were similar with no significant difference in the volume of distribution and clearance of CsA demonstrated between the CF and non-CF groups. The mean daily dose of oral CsA in 7 CF subjects (23.3 mg·kg−1) was significantly higher than the 3 non-CF heart-lung recipients (4.8 mg·kg−1). The mean maximum blood concentration of CsA for the oral dose was 776 ng·ml−1 for the 7 CF subjects, which was comparable with the mean peak values of 789 ng·ml−1 for the 3 non-CF control subjects. Poor enteral absorption of CsA probably accounts for the significantly lower mean bioavailability in the 7 CF subjects (14.9%) compared with the 3 non-CF control subjects (39.4%).
The effects on the bioavailability of oral CsA solution by pancreatic enzymes (Creon) and histamine-2 antagonist (ranitidine) were also evaluated in the 7 CF subjects. No significant difference was demonstrated.
Similar content being viewed by others
References
Reitz BA, Bieber CP, Raney A, et al (1981) Orthotopic heart and combined heart and lung transplantation with cyclosporin-A immune suppression. Transplant Proc 13: 393–396
Kahan BD (1987) Immunosuppressive therapy with cyclosporin for cardiac transplantation. Circulation 75: 40–56
Wadhwa NK, Schroeder TJ, O'Flaherty E, et al (1987) The effect of oral metoclopramide on the absorption of cyclosporin. Transplant Proc 19: 1730–1733
Venkataramanan R, Ptachcinski RJ, Burckart GJ, Gray J, Van Thiel DH, Starzl TE (1985) Cyclosporin bioavailability in liver disease. Drug Intell Clin Pharmacol 19: 451
Tredger JM, Naoumov CM, Steward CM, et al (1988) Influence of biliary T tube clamping on cyclosporin pharmacokinetics in liver transplant recipients. Transplant Proc 20: 512–515
Grevel J (1988) Significance of cyclosporin pharmacokinetics. Transplant Proc 20: 428–434
Scott JP, Higenbottam TW, Hutter J, et al (1988) Heart-lung transplantation for cystic fibrosis. Lancet II: 192–194
Zentler-Munro PL, Northfield TC (1987) Pancreatic enzyme replacement — applied physiology and pharmacology (review). Aliment Pharmacol Ther 1: 575–591
Stead RJ, Skypala I, Hodson ME, et al (1987) Enteric coated microspheres of pancreatin in the treatment of cystic fibrosis. Comparison with a standard enteric coated preparation. Thorax 42: 533–537
Yacoub MH, Banner NR, Khaghani A, et al (1990) Combined heart and lung transplantation for cystic fibrosis and subsequent Domino cardiac transplantation. J Heart Transplant 9: 459–467
Wong PY, Ma J (1990) Specific and nonspecific monoclonal 125I-Incstar assays. Transplant Proc 22: 1166–1170
Johnston A, Woollard RC (1983) STRIPE: an interactive computer program for the analysis of drug pharmacokinetics. J Pharmacol Methods 9: 193–199
Ptachcinski RJ, Venkataramanan R, Burckart GJ, et al (1986) Clinical pharmacokinetics of cyclosporin. Clin Pharmacokinet 11: 107–132
Cooney GF, Fiel SB, Shaw LM, Cavarocchi NC (1990) Cyclosporin bioavailability in heart-lung transplant candidates with cystic fibrosis. Transplantation 49: 821–823
Mancel-Grosso V, Bertault-Peres P, Barthelemy A, Chazalette JP, Durand A, Noirclerc M (1990) Pharmacokinetics of cyclosporine A in bilateral lung transplantation candidates with cystic fibrosis. Transplant Proc 22: 1706–1707
Tan KKC, Strickland SE, Trull AK, et al (1990) Altered pharmacokinetics of cyclosporin in heart-lung recipients with cystic fibrosis. Ther Drug Monit 12: 520–524
Venkataramanan R, Burckart GJ, Ptachcinski RJ, et al (1986) Cyclosporin pharmacokinetics in heart transplant patients. Transplant Proc 18: 768–770
Spino M, Chai RP, Isles AF, et al (1984) Cloxacillin absorption and disposition in cystic fibrosis. J Paediatr 105: 829–835
Finkelstein E, Halik J (1979) Aminoglycosides clearance in patients with cystic fibrosis. J Paediatrics 94: 163–164
Levy J, Smith AL, Koup JR et al (1984) Disposition of tobramycin in patients with cystic fibrosis. J Paediatr 105: 117–124
Isles A, Spiro M, Tabachnik E, et al (1983) Theophylline disposition in cystic fibrosis. Am Rev Respir Dis 127: 417–421
Weizman Z, Durie PR, Kopelman H, Vesely S, Forstner GG (1986) Bile acid secretion in cystic fibrosis — evidence for a defect unrelated to fat malabsorption. Gut 27: 1043–1048
Robb TA, Davidson GP, Kirubakaran C (1985) Conjugated bile acids in serum and secretions in response to cholecystokinin/secretin stimulation in children with cystic fibrosis. Gut 26: 1246–1256
Daring PB, Lepage G, Leroy C, Masson P, Roy CC (1985) Effect of taurine supplements on fat absorption in cystic fibrosis. Paediatr Res 19: 578–582
Quinton PM (1990) Cystic fibrosis: a disease in electrolyte transport. FASEB J 4: 2709–2717
Scott JP, Smyth RL, Higenbottam TW, McGoldrick JP, Wallwork J (1989) Cyclosporin dosing in cystic fibrosis after transplantation. Transplantation 48: 543–544
Cox KL, Isenberg JN, Ament ME (1982) Gastric acid hypersecretion in cystic fibrosis. J Paediatr Gastroenterol Nutr 1: 559–565
Kopelman H, Durie P, Gaskin K, Weizman Z, Forstner G (1985) Pancreatic fluid secretion and protein hyperconcentration in cystic fibrosis. N Engl J Med 312: 329–334
Burckart G, Starzl T, Williams L, et al (1985) Cyclosporin monitoring and pharmacokinetics in paediatric liver transplant patients. Transplant Proc 17: 1172–1175
Sokol RJ, Johnson KE, Karrer FM, et al (1991) Improvement of cyclosporin absorption in children after liver transplantation by means of water soluble vitamin E. Lancet 338: 212–214
Congden PJ, Bruce G, Rothburn MM, et al (1981) Vitamin status in treated patients with cystic fibrosis. Arch Dis Child 56: 708–714
Sokol RJ, Heubi JE, Butler-Simon N, McClung HJ, Lilly JR, Silverman A (1987) Treatment of vitamin E deficiency during chronic childhood cholestasis with oral d-alpha tocopheryl polyethylene glycol-1000 succinate. Gastroenterology 93: 975–985
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Tsang, V.T., Johnston, A., Heritier, F. et al. Cyclosporin pharmacokinetics in heart-lung transplant recipients with cystic fibrosis. Eur J Clin Pharmacol 46, 261–265 (1994). https://doi.org/10.1007/BF00192559
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00192559