Hartner, C

Iwatsuki, S

Koneru, B

Starzl, TE

English

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004 J -133, /88/4505 J(XlJ$02.00/0 TRANSPLANTATION Copyright «; 19M by Tb .. Williams & tilkin~ Co. Vol. 45. 1001, No.5, May 1988 Printed in USA. Transplantation LETTER TO THE EDITOR EFFECT OF DANAZOL ON CYCLOSPORINE PHARMACOKINETICS' Danazol, a derivative of ethisterone is an inhibitor of pitui-tary gonadotrophins and a weak androgen. It is increasingly used in endometriosis and fibrocystic mastopathy. There has been only a single report of its effect on cyclosporine (CsA *) pharmacokinetics in a kidney transplant recipient in the liter-ature in English (1). One of our patients, a 47-year-old woman with primary biliary cirrhosis, received an orthotopic liver transplant in January 1986. The patient began having irregular heavy vaginal bleeding in April 1986. At this time, she was taking CsA 150 mg p.o. b.i.d.; prednisone 10 mg q.d., azathioprine 25 mg q.d., and lasix 40 mg q.d. She was placed on intermittent norethin-drone (Norlutate) 15 mg p.o. q.d. This did not have any effect on her vaginal bleeding, cyclosporine levels, or liver functions over a period of 3 months. The patient was eventually started on danazol 200 mg p.o. q.i.d. Within days of starting danazol her CsA levels increased, along with a rise in transaminase values. There was no change in bilirubin and alkaline phospha-tase levels (Table 1). After stopping danazol, CsA, transami-nases, and creatinine levels reached previous values_ The rise in CsA levels could reflect increased intestinal absorption or decreased breakdown in the liver. There have been reports of inhibition by some sex steroids of hepatic microsomal enzyme systems (2) that increases CsA levels_ It is more than likely that the rise in CsA levels seen in our patient is a result of a decrease in CsA breakdown by the liver rather than increased absorption. In a series of nontransplant patients danazol has been reported to cause elevation of hepatic trans-I This work was supported by Research Grants from the Veterans Administration, and by Project Grant AM 29961 from the National Institutes of Health, Bethesda, MD. • Abbreviations used: CsA, cyclosporine; SGOT, serum glutamic oxaloacetic transaminase; RIA, radioimmunoassay; SGPT, serum glu-tamic pyruvic transaminase. aminases in a small minority of cases when given in doses of 800 mg/day (3). The other possibility, that hepatic transami-nase elevations in our patient are secondary to CsA hepato-toxicity, is unlikely because of the absence of changes in bili-rubin and alkaline phosphatase (4). The progestational agent norethindrone did not affect the CsA levels or liver functions when given intermittently. Hence caution is indicated when starting patients taking CsA on danazol or other sex steroids. CsA levels should be measured and liver function tests per-formed frequently. BABURAO KONERU 2 CAROLYN HARTNER SHUNZABURO Iw ATSUKI THOMAS E. STARZL The Department of Surgery University Health Center of Pittsburgh University of Pittsburgh The Veterans Administration Medical Center Pittsburgh, Pennsylvania 15213 2 Address correspondence to: Baburao Koneru. 4 West Falk Clinic, 3601 Fifth Avenue, Pittsburgh, PA 15213. REFERENCES 1. Ross WB, Roberts D, Griffin PJA, Salam an JR. Cyciosporine interaction with Danazol and Norethisterone. Lancet 1986; 1: 330. 2. Maurer G. Metabolism of cycJosporine. Transplant Proc 1985 17(suppl 1): 19. 3. Spooner JB. Classification of side effects to Danazol therapy. J Int Med Res 1977; 5(suppl 3): 15. 4. Lorber MI, VanBuren CT, Flechner SM, Williams C, Kahan BD. Hepatobiliary and pancreatic complications of cyciosporine ther-apy in 466 renal transplant recipients. Transplantation 1987; 43: 35. TABLE L Cyclosporine levels, liver functions, and creatinine values before, during, and after danazol therapy esA level (RIA) Total SGPTjSGOT Alkaline Creatinine Date (ng/ml) bilirubin (UlL) phosphatase (mg/dl) (mg/dl) (V/L) 3/23/87 305 0.7 4/9 68 2'} 4/13/87 319 0.8 10/15 58 2.2 5/14/87 238 0.6 11/11 65 2.2 Norethindrone given intermittently 6/1/87 224 0.6 8/5 60 2. I Danazol 200 mg q.i.d. 7/31/87 8/11/87 812 8/14/87 724 8/25/87 1034 0.7 253/111 62 2.9 Danazol stopped 8/27/87 734 0.6 249/90 52 2.6 CsA dose to 125 mg bj.d. 8/31/87 595 0.5 122/29 55 2.3 9/21/87 269 0.6 21/10 68 2.3 10/5/87 287 0.5 21/17 71 2.3 1001 

Effect of danazol on cyclosporine pharmacokinetics

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Effect of danazol on cyclosporine pharmacokinetics

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