Herbal teas interfere with cyclosporin levels in renal transplant patients

Rainer Nowack1 and Barbara Nowak2

Dialysis-Centers 1 Lindau/Bodensee and 2 Immenstadt i.Allgäu, Germany

Correspondence and offprint requests to: Dr R. Nowack, Dialysezentrum Lindau, Friedrichshafener Str. 82, D-88131 Lindau, Germany. Email: info{at}dialyse-lindau.de

Keywords: cyclosporin; cytochrome P450 enzymes; herbal teas; herb–drug interaction; pharmacokinetics



   Introduction
 Top
 Introduction
 Cases
 Discussion
 References
 
After a successful renal transplantation, a high fluid intake of 2–3 l daily is generally advised to achieve a steady urine flow. To reach that goal, dieticians recommend herbal teas, since they regard them as biologically inert; in contrast to black tea, coffee, alcoholics or commercial fruit juices, which are either psychotropic or rich in calories.

However, herbal teas contain plant constituents of biological relevance for the consumer, and especially for transplanted patients treated with immunosuppressive medication.

We present here three renal transplant patients who drank herbal teas with a marked influence on cyclosporin metabolism.



   Cases
 Top
 Introduction
 Cases
 Discussion
 References
 
The first patient was a 48-year-old woman (weight 56 kg, height 165 cm) who received a cadaveric renal allograft in September 2000. After two severe rejection episodes, graft function had stabilized at a serum creatinine of 1.2–1.4 mg/dl and she received maintenance immunosuppression with cyclosporin, mycophenolate mofetil (MMF) and tapered steroids which were discontinued after 14 months. Her additional medication consisted of pravastatin, valsartan and hydrochlorothiazide.

During the first year post-transplant, cyclosporin trough levels of 110–140 µg/l were maintained by 2 x 110 mg/day. Gradually the levels declined although the dosage was subsequently increased to 2x150 mg/day. There were no signs of rejection or cyclosporin toxicity in a transplant biopsy performed 18 months post-transplant.

Despite another dosage adjustment to 2 x 170 mg/day, target trough levels were constantly missed, with actual trough levels ranging between 80 and 85 µg/l.

The patient denied taking any additional medication or herbal drugs. She reported, however, drinking ~2 l daily of a certain herbal tea following the advice of the transplant unit. The tea (Thüringer 9-Kräuter Tee) is produced from the following herbs: peppermint (Mentha piperata); bramble (Rubus fruticosus); camomile (Matricaria recutita); balm (Melissa officinalis); coriander (Coriandrum sativum); sandalwood (Santalum album); orange peel (Citrus aurantium); ratanhia root (Krameria triandra); and anise (Pimpinella anisum).

Although none of these herbs were known to the authors to decrease cyclosporin levels, the patient was asked to replace this tea by mineral water, while leaving the cyclosporin dosage at 2x150 mg/day. After 2 weeks, her cyclosporin trough levels started to increase. When trough levels of 170 µg/l were reached after 6 weeks, we agreed that the patient could return to her tea-drinking habit. With an unchanged dosage of cyclosporin, trough levels fell within 2 weeks to 110 µg/l.

When the peak levels of cyclosporin were reached, the patient complained about muscular pain and weakness. Creatinine kinase was increased to 340 U/l (normal range <100) and rhabdomyolysis was diagnosed, probably induced by pravastatin (10 mg/day).

The second patient was a 37-year-old male (76 kg, 179 cm) of Armenian ancestry. He had received a cadaveric renal transplant in December 2000 and was on maintenance immunosuppression with azathioprin and cyclosporin. Azathioprin was later replaced by MMF.

After stepwise reduction of cyclosporin dosage, trough levels of 180–200 µg/l were maintained by 2x75 mg/day cyclosporin. The patient reported drinking at least 1–1.5 l daily of a single brand of camomile tea. He was advised to refrain from consumption of this tea, and he chose other beverages instead, mainly rose-hip tea.

After a few weeks, cyclosporin trough levels declined markedly to the range of 100–120 µg/l, although the dosage was left unchanged. When these levels finally dropped to 50 µg/l, the cyclosporin dosage was increased to 2x100 mg/day.

The third patient was a 33-year-old man (79 kg, 180 cm), who received a cadaveric renal transplant in August 2000 and was on immunosuppression with cyclosporin and MMF. His cyclosporin trough levels ranged from 118 to 155 µg/l with a dosage of 2x100 mg. From March 2002, trough levels were constantly raised above 200 µg/l. His medication was unchanged and he was not taking any alternative medicine. He had, however, started to drink large quantities of a so-called wildfruit tea drink (Früchtezauber) [ingredients: sugar, dextrose, acidifier citric acid, hibiscus extract (2%), flavouring, vitamin C, rose-hip extract (0.1%)], as well as a lemon tea drink [ingredients: sugar, dextrose (20%), acidifier citric acid, black tea extract cold water soluble (1.28%), vitamin C, lemon fruit powder, flavouring].

After the patient discontinued these teas, following our advice, a constant decrease of cyclosporin trough levels back to 90 µg/l occurred within a few weeks. The cyclosporin dosage was then moderately increased to 2x110 mg/day and the average trough levels have remained at ~120 µg/l since that time.



   Discussion
 Top
 Introduction
 Cases
 Discussion
 References
 
Cyclosporin has a narrow therapeutic range, and maintenance immunosuppression after renal transplantation needs careful blood concentration monitoring. Concomitant medication and many plant constituents in food or drinks can interfere with cyclosporin's main metabolic pathway by cytochrome P450 (CYC P450) enzymes [1,2] and change its bioavailability.

Grapefruit juice inhibits the enzymatic activity and decreases the drug's first pass effect, which leads to increased trough levels [3]. The herbal antidepressant St John's wort stimulates CYC P450 activity and can seriously decrease cyclosporin levels [4]. Since many other plant ingredients have been shown to affect CYC P450 enzymes experimentally [5], many more than the already described herb–drug interactions can be expected.

Surprisingly, herbal teas have been poorly studied in this respect. Worldwide, many brands from a vast number of plant species are produced. Renal transplant recipients tend to consume significant quantities of herbal teas.

In the three renal transplant patients presented here, herbal teas seem to have modified the cyclosporin metabolism considerably.

In the first patient, avoidance of the tea for several weeks led to an increase of cyclosporin trough levels, and a subsequent fall of levels occurred after re-exposure to the tea. Which one of the nine herbal ingredients of the tea lowered blood levels of cyclosporin is unresolved, notably because two herbs (orange peel, camomile) are known to raise cyclosporin levels, instead of lowering them.

In the second patient, avoidance of camomile tea was followed by a drop of trough levels of cyclosporin. This is in accordance with data already documenting an inhibitory effect of camomile on CYC P450 enzymes in vitro [5].

In the third patient, discontinuation of fruit teas lowered cyclosporin trough levels markedly. These drinks were produced from fruit extracts for instant preparation. Nevertheless, they appear to contain enough bioactive ingredients to affect cyclosporin metabolism. The authors assume that ingredients of citrus are responsible for the effect on cyclosporin [6].

The influence of herbal teas on cyclosporin metabolism was best illustrated in the first patient; however, the decline in trough levels after elimination of the teas was significant and long-lasting in the other two patients as well. No concomitant changes in medication or nutrition occurred to the best of our knowledge, and the methodology of monoclonal cyclosporin assays was not changed.

In the first patient, rhabdomyolysis occurred together with steeply increasing cyclosporin trough levels following her abstinence from tea. As rhabdomyolysis is a reported side effect of HMG-CoA reductase inhibitors [7], the pravastatin was temporarily withdrawn and at the same time re-exposure to the tea was allowed. Cyclosporin levels fell promptly and pravastatin could soon be re-administered at the usual dosage without further muscular abnormalities. Cyclosporin and pravastatin are both substrates of CYC P450 enzymes and mutually modify their blood concentrations if co-administered [8]. However, the risk for pravastatin-induced rhabdomyolyis is lower than for other statins because of its lesser dependence on CYC P450 metabolism [9]. The combined occurrence of increasing cyclosporin levels and rhabdomyolysis might be explained by an as yet unknown stimulatory constituent affecting CYC P450 enzymes present in the tea, which lowered cyclosporin and pravastatin concentrations in blood, as long as the tea was consumed.

The case reports suggest that many more plant-derived products might modify cyclosporin metabolism than previously expected.

Recent research suggests that a traditional English breakfast with Earl Grey tea and toast with bitter orange marmalade should markedly modify cyclosporin metabolism. The flavonoid naringenin and the furanocumarin bergamottin are strong inhibitors of one subfamily of CYC P450 enzymes in grapefruit juice [10] and also occur in bitter oranges (Citrus aurantium), as well as in their variant bergamot, which flavours Earl Grey tea. In animal experiments, bitter oranges induced severe cyclosporin intoxication at an otherwise safe cyclosporin dosage [11].

Quercetin is another example, being present, for example, in onions, red wine and many other foods, and significantly decreases cyclosporin bioavailability by inhibition of CYP3A4 [12].

Research in this field progresses, and the data cited above are only eclectic. Patients and physicians should be aware of this problem. Dosage adjustment might be necessary after major dietary modifications, and herbal teas should not be regarded as biologically inert [13].

Conflict of interest statement. None declared.



   References
 Top
 Introduction
 Cases
 Discussion
 References
 

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Received for publication: 25. 2.05
Accepted in revised form: 14. 6.05





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