Interaction between estradiol and tacrolimus in kidney-transplanted menopausal women

Sir,

Hormone replacement therapy for symptoms caused by oestrogen deficiency is often used by menopausal women. Transdermal administration is regularly used by means of a dermal application gel. Its active principle, the synthesis 17β estradiol, is a well-known substance known as an inhibitor of the microsomial cytochrome P450 enzymatic system.

We present the case of a kidney transplant woman who faced a brutal degradation of her graft function consequent to an increase of her tacrolimus plasma level.

This 65-year-old patient had benefited from a kidney transplant as a consequence of renal insufficiency due to hyperuricaemia-induced interstitial nephropathy (uromoduline gene mutation). Her medical history also included hypertension, hysterectomy for fibroma and partial thyroidectomy. Her treatment included tacrolimus 9 mg/day, mycophenolic acid 540 mg/day, prednisolone 4 mg/day, lisinopril 20 mg/day, atorvastatin 10 mg/day, l-thyroxine 100 mg/day and alprazolam 0.5 mg/day. She had a normal post-transplant evolution with good renal function (creatinine 1.1 mg/dl, GFR estimated according to MDRD 53 ml/min/1.73 m², plasma tacrolimus trough levels ranging between 5.0 and 7.5 ng/ml).

Her renal function suddenly deteriorated 10 days after a gynaecological consultation, with a very high tacrolimus plasma level: creatinine increased to 1.6 and 2 mg/dl, GFR decreased to 28 ml/min/m² and tacrolimus plasma trough levels reached 14.2 and 18.3 ng/ml. No other cause of graft-function loss was detected: an echography with Doppler was normal; no urinary infection was found. A thorough investigation of her medication revealed a new oestrogen gel-based treatment (Estreva 0.1%, Merck, France) requesting daily application of 0.5 mg/day (one-third of the recommended doses). Despite the small estradiol doses, plasma tacrolimus concentrations apparently significantly increased because of medical interaction between tacrolimus and the oestrogen preparation. A drastic reduction (60%) in the daily doses of tacrolimus was necessary to reach the therapeutical plasma concentrations again: the tacrolimus plasma trough level reached 6.4 ng/ml, serum creatinine 1.3 mg/dl and eGFR 44 ml/min/m², 2 weeks after a progressive reduction in the tacrolimus dosage.

Both tacrolimus and estradiol are metabolized through the CYP450 3A4 enzyme complex [1,2,5]. Tacrolimus is a well-known strong inhibitor of the 2-estradiol metabolization phases (hydroxylation and glucuronidation) [2,4], delaying its elimination. While estradiol inhibits hepatic as well as intestinal CYP450 3A4 [3], it induces a lowering in the tacrolimus metabolism. This inhibition shows an inter-individual variability [3]. The transdermic administration avoids the hepatic ‘1st passage’ phenomenon, which explains the fact that even small doses are sufficient to create a systemic effect.

Co-administration of tacrolimus with oestrogen is possible, but a close monitoring of tacrolimus trough levels and renal function is necessary. Even small doses of estradiol can create severe interactions with tacrolimus; therefore, clinicians should be aware of this harmful drug interaction in order to avoid potential renal graft dysfunction.

Conflict of interest statement. None declared.