Interaction between theophylline and tacrolimus in a renal transplant patient

Samir Boubenider1,, Isabelle Vincent2, Olivier Lambotte1, Sandrine Roy2, Christian Hiesse1, Anne-Marie Taburet2 and Bernard Charpentier1

1 Service de Néphrologie and 2 Department of Clinical Pharmacy, Bicêtre Hospital, Université Paris XI, Kremlin Bicêtre, France

Keywords: cytochrome P450; erythrocytosis; erythropoietin; tacrolimus; theophylline; transplantation



   Introduction
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 Introduction
 Case
 Discussion
 Conclusions
 References
 
Tacrolimus is a calcineurin inhibitor. It is a potent immunosuppressive drug which has been approved in several countries. It is currently indicated for both prophylaxis and treatment of allograft rejection. Metabolism of tacrolimus occurs primarily in the liver via the cytochrome P450-3A4 (CYP3A4) enzyme system. There are many potential drugs interacting with tacrolimus which should be used with caution, particularly in patients who are concurrently taking CYP3A4 inhibitors or inducers [1,2]. We report herein the first case of tacrolimus and theophylline interaction in a renal transplant recipient.



   Case
 Top
 Introduction
 Case
 Discussion
 Conclusions
 References
 
In March 1998, a 33-year-old man with end-stage renal disease due to diabetic nephropathy received a cadaveric kidney allograft. He had no history of cardiac or pulmonary disease. Post-transplantation maintenance immunosuppressive therapy included tacrolimus (7 mg/d), azathioprine (75 mg/d) and prednisone (7.5 mg/d). The patient was also receiving insulin with no other drugs. The post-operative course was uneventful with no rejection episodes and no hypertension. At discharge, the serum creatinine was 110 µmol/l. White blood count (WBC), haemoglobin (Hb) and haematocrit (Hct) values were 3870/mm3, 12.3 g/dl and 43% respectively. The tacrolimus trough blood concentration (tacrolimus TBC) assayed using a microparticle enzyme immunoassay and IMx autoanalyser, was stable within normal ranges (normal range, 5–15 ng/ml).

In May 1998, the patient developed post-renal-transplant erythrocytosis. Hb and Hct values rose to 19.4 g/dl and 54% respectively. WBC remained within normal range at 8340/mm3. Isotopic measurement of the red cell mass confirmed absolute moderate polycythaemia. Serum erythropoietin (Epo) level was increased at 37 mIU/ml (normal 10–25). The kidney, liver, and spleen sonograms were normal. Allograft and native renal artery Doppler ultrasound images did not reveal any stenosis. In order to reduce Epo production, the angiotensin-converting enzyme inhibitor (ACEi) enalapril was added to the treatment, but without success. During a period of 3 months, eight phlebotomy sessions (300–400 ml/session) were used to control Hb levels. In October 1998, in order to reduce the need for phlebotomies, theophylline (600 mg/day) was added to the ACEi. After 1 month, serum creatinine and tacrolimus TBC rose to 145 µmol/l and 16 ng/ml respectively. Therefore, the theophylline dose was reduced to 300 mg/day four times weekly, which led to a significant reduction in the number of necessary phlebotomy sessions. Only two further phlebotomies were required to keep Hb and Hct levels within acceptable ranges. One month later, serum creatinine and tacrolimus TBC increased further to 175 µmol/l and 48.5 ng/ml respectively (Figure 1Go). Although theophylline serum concentrations remained low (2 and 6.7 mg/l; normal range 10–15), this drug was discontinued and both renal function and tacrolimus TBC rapidly returned to normal values. ACEi was replaced without further success by losartan, a specific angiotensin-II (A-II) receptor antagonist (25 mg/d).



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Fig. 1. Renal function and FK506 TBC pre- and post-theophylline therapy.

 
Therefore, the patient was readmitted for reintroduction of theophylline at a lower dose. At this time, the pharmacokinetics of tacrolimus were assessed. The patient was kept on the same doses of maintenance anti-rejection treatment, insulin therapy and losartan. Theophylline (125 mg/d) was administered from day one to day 4. Tacrolimus pharmacokinetics were assessed at day 0 (before theophylline administration) and after 4 days of theophylline administration (day 4) respectively. Blood samples were taken at days 0 and 4, pre- and post-tacrolimus intake, and every 2 h for 10 h post-tacrolimus initiation. Theophylline coadministration led to an increase in the tacrolimus area under the curve from 0 to 10 h (AUC 0–10 h: 25 vs 142 ng/h/ml). While the maximum concentration increased from 19.3 to 37.4 ng/ml (Figure 2Go), no significant changes in renal function were noted. Theophylline serum concentration determined by HPLC, before, or during tacrolimus administration, were at low values. The peak theophylline concentration was 4.3 mg/l, occurring at 2 h post-theophylline administration. A few days after discharge, theophylline was withheld because of gastric discomfort. Erythrocytosis is currently controlled with routine phlebotomy sessions and losartan.



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Fig. 2. Pharmacokinetics of FK506 with and without theophylline.

 



   Discussion
 Top
 Introduction
 Case
 Discussion
 Conclusions
 References
 
Post-renal transplant erythrocytosis is a well-known complication, which usually occurs within the first 2 years after surgery [3,4]. About 10–20% of kidney transplant patients develop this complication [5]. Various causes have been suggested to explain this phenomenon [47]. It is thought to be a self-limiting process that requires appropriate management, including supportive therapy (phlebotomy) and a pharmacological approach in order to block Epo secretion. Options in this regard have included ACEi, specific A-II receptor antagonists and theophylline [810]. A number of clinically relevant interactions between calcineurin inhibitors and co-administered drugs have been reported [1,2,11]. However, to the best of our knowledge, no case of calcineurin inhibitor–theophylline interaction has been previously reported.

It is well known that CYP3A4 is primarily responsible for tacrolimus liver biotransformation. Substances known to inhibit CYP3A4 may decrease tacrolimus metabolism and thereby increase its blood concentrations. Aminophylline is rapidly hydrolysed during its first pass, which leads to the formation of the active compound theophylline [12]. CYP1A2 is considered to be the most important enzyme involved in theophylline liver metabolism [13], while CYP3A4 has a minor role in theophylline metabolism. It is therefore surprising that the tacrolimus–theophylline interaction appears in this matter.

In vitro, theophylline concentration, at 10 times molar excess of tacrolimus, barely inhibits (by 5%) CYP3A4 tacrolimus metabolism [14]. In the present case, at the time of interaction and despite low-dose theophylline, the calculated theophylline–tacrolimus concentration molar ratio was about 750. If the above in vitro findings are taken into consideration, this interaction may be explained by the very high ratio of theophylline/tacrolimus molar concentrations, as in fact expected when these two drugs are used concomitantly.



   Conclusions
 Top
 Introduction
 Case
 Discussion
 Conclusions
 References
 
Theophylline interacts with tacrolimus liver metabolism by inhibiting the CYP3A4. Although in the present case a low theophylline dose led to tacrolimus AUC increase, renal function remained stable. Therefore low dose theophylline can be used in transplant patients with erythrocytosis, provided that tacrolimus concentrations are closely monitored.



   Notes
 
Correspondence and offprint requests to: Dr S. Boubenider, Service de Néphrologie, CHU de Bicêtre, 78 Rue du Général Leclerc, F-94275 Kremlin Bicêtre, France. Back



   References
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 Introduction
 Case
 Discussion
 Conclusions
 References
 

  1. Furlan V, Perello L, Jacquemin E, Debray D, Taburet AM. Interaction between FK506 and rifampicin or erythromicin in pediatric liver recipients. Transplantation1995; 5: 1217–1218
  2. Shapiro R, Venkataramanan R, Warty VS et al. FK506 interaction with danazol. Lancet1993; 341: 1344–1345
  3. Tatman AJ, Tucker B, Amess JAL, Cattel WR, Baker LRI. Erythraemia in renal transplant recipients treated with cyclosporine. Lancet1988; 2: 1279–1280
  4. Ramos EL, Balagtas R. Post-transplant erythrosis. J Nephrol1992; 5: 9–13
  5. Gaston RS, Julian BA, Curtis JJ. Posttransplant erythrocytosis: An enigma revisited. Am J Kidney Dis1994; 24: 1–11[ISI][Medline]
  6. Thevenod F, Radtke HU, Grutzmacker P et al. Deficient feedback regulation of erythropoiesis in kidney transplant patients with polycythemia. Kidney Int1983; 24: 227–232[ISI][Medline]
  7. Fridman S, Nyberg G, Blohme I. Erythrocytosis after renal transplantation: Treatment by removal of the native kidney. Nephrol Dial Transplant1990; 5: 969–973[Abstract]
  8. Parazella M, McPhedran P, Kliger A, Lorber M, Levy E, Bia JM. Enalapril treatment of posttransplant erythrocytosis: efficacy independent of circulating erythropoietin levels. Am J Kidney Dis1995; 26: 495–500[ISI][Medline]
  9. Klaassen RJL, Gelder TV, Rischen-vas J, Deinum J, Man In't Veld AJ, Weimar W. Losartan, an angiotensin-II receptor antagonist, reduces hematocrits in kidney transplant recipients with posttransplant erythrocytosis. Transplantation1997; 64: 780–782[ISI][Medline]
  10. Bakris GL, Sauter ER, Hussey JL, Fisher JW, Gaber O, Winsett R. Effects of theophylline on erythropoietin production in normal subjects and in patients with erythrocytosis after renal transplantation. N Engl J Med1990; 323: 86–90[Abstract]
  11. Miels L, Venkatamanan R, Yokoyama I, Warty VS, Starzl TE. Interaction between FK506 and clotrimazole in liver transplant recipient. Transplantation1991; 52: 1086–1087[ISI][Medline]
  12. Troger U, Meyer FP. Influence of endogenous and exogenous effectors on the pharmacokinetics of theophylline. Clin Pharmacokinet1995; 28: 287–314[ISI][Medline]
  13. Tjia JF, Colbert J, Back DJ. Theophylline metabolism in human liver microsomes: inhibition studies. J Pharmacol Exp Ther1996; 216: 912–917
  14. Marsuda H, Iwasaki K, Shiraga T, Tozuka Z, Hafa T, Guengerich P. Interaction of FK506 (tacrolimus) with clinically important drugs. Res Commun Chem Pathol Pharmacol1996; 82: 209–216
Received for publication: 17. 9.99
Revision received 3. 3.00.



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