Cyclosporine, Psoriasis, and Grapefruit Juice

Cyclosporine (CS), a potent immunosuppressive peptide, was discovered by Sandoz in 1975.  Clinical testing showed that it was very effective for preventing rejection of life-saving organ transplants such as kidney, heart, liver, and bone marrow.  Investigators also noted the impressive ability of CS to clear up any psoriasis on the skin of the transplant recipients.  Subsequent studies of CS in the treatment of severe psoriasis confirmed significant efficacy of the drug in a dose-related fashion compared to placebo.  Cyclosporine was eventually approved for the treatment of psoriasis in 1997 at a daily dosage of 3-5 mg/kg/day.  It is also used today by

Severe psoriasis before treatment

rheumatologists to treat rheumatoid and psoriatic arthritis. After more experience in the clinic, it became apparent that CS commonly caused two significant adverse effects: hypertension and kidney damage.  The blood pressure could be controlled by the calcium channel-blocking drugs, and kidney failure could be prevented temporarily with fish oil supplements. Ultimately, dermatological societies in the U.S. and Europe recommended limiting the use of CS for psoriasis to one to two years’ duration while seeking other less toxic solutions.

After treatment with cyclsporine 5 mg/kg/day for 3 months

Currently, CS is infrequently used by dermatologists to treat psoriasis because of the popularity of the biologic drugs (for example, Enbrel, Humira, Stelara) which are somewhat easier to use in practice and are given by injection.  The “biologics” are also immunosuppressive, but in a more selective way than CS.  However, they do increase the risk of serious infections, skin cancers, and rarely, lymphoma.  Biologics do not affect the kidney or blood pressure. Many of my own patients have made the transition from CS to biologics or other treatments, but some have chosen to continue with CS for longer than two years out of necessity because biologics have not been completely effective for them, or simply because they have not experienced any side effects of CS and do not wish to take the risks of a new drug. The formulation of CS approved for psoriasis is a modified emulsion that gives better and more consistent absorption and blood levels than the original.  The brand name is Neoral, but there are also generic brands.  Although less expensive than biologics, modified CS is not a cheap drug.  For example, the estimated annual cost of treatment including office visits and blood tests exceeds the cost of phototherapy given in the office. Because of the expense of the drug, methods to cut costs were explored.  It was known that CS is metabolized by the CYP3A4 enzyme system in the wall of the small intestine and the liver.  By co-administering a drug that competes with the same pathway or inhibits the enzyme, the absorption of CS and blood concentrations could be increased.  Some of the anti-fungal drugs can do this, but they have liver toxicity of their own and add to the expense. It was found that 8 ounces of grapefruit juice taken simultaneously with CS inhibits CYP3A4 in the gut wall resulting in reduced first-pass metabolism, higher bioavailability, and an increased peak of serum concentration of the drug.  This effect can also be seen with other relevant drugs besides CS: prednisone, estrogen, nifedipine, colchicine, and some of the lipid-lowering statins. While  it is not known for certain which component of grapefruit juice is responsible for this effect, furocoumarin compounds are believed to play a major role with flavonoids playing a secondary role.  It is now generally recommended by pharmacists to avoid drinking grapefruit juice when taking a drug that is metabolized mainly by CYP3A4 because brands of juice and batches of the same brand vary in their potency and are not standardized to this detail.  Similar drug interactions have not been noted with other citrus fruit juices. I found it interesting and hopeful that researchers with the University of Florida are addressing the issue by developing hybrids between grapefruit and pummelo that have lower furocoumarin content.  Juice samples were tested for their overall effect on enzyme  activity.  Hybrids selected for release will be the ones with the lowest inhibitory effect. grapefruitThus, it is possible that in the future patients may be able to drink their favorite juice along with medicines such as CS, allowing them to increase their blood levels in a safe, standardized manner while taking less of the drug itself.


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