Cyclosporine is an immunosuppressive agent administered to solid organ transplant recipients to prevent and treat transplant rejection, is an antirejection drug. Cyclosporine is prescribed for liver, intestinal, lung, and heart transplant recipients, and can be used to manage severe autoimmune conditions, such as atopic dermatitis and rheumatoid arthritis. The drug is metabolized by gastrointestinal CYP3A isozymes, predominantly CYP3A4 and CYP3A5.

The impact of variants within CYP3A5 and CYP3A4 on cyclosporine efectivennes has been controversial for many time but during the latest years several clinical studies have found evidences linking polymorphisms in these cytochromes with the pharmacokinetic and pharmacodynamic of the drug.

A study in 110 renal recipients found that CYP3A5*3 homozygotes have higher dose-adjustment trough concentrations than heterozygotes, and another study in 91 bone marrow recipients reported that *3 homozygotes had greater dose-adjustment trough concentrations on days 1–10 of treatment, and greater dose requirements on days 16–30, as compared with *1 homozygotes. Thus, it was clear that the CYP3A5 allele affects in pharmacokinetics when used as an immunosuppressant for transplantation and that CYP3A5 *3 /* 3 homozygotes need a higher dose of cyclosporin. In addition, it is important to note that the allele frequency of CYP3A5 * 3 function loss is very high in the general population, about 90% in Caucasians, Americans and Europeans, being much less frequent in Africans, so the presence of poor metabolizers is very common and can be said to have almost supplanted the ancestral CYP3A5 allele. It is therefore very common for transplanted patients who are prescribed cyclosporin to have many adverse effects if they have not been genotyped and dosed previously. The reason that *3/*3 homozygotes need more doses of cyclosporin is explained because the *3 allele produces a smaller amount of cytochrome than the wild type allele does, so the metabolization rate is slower.

In another relevant clinical study in transplanted kidney patients who have been given cyclosporine as an immunosuppressant those patients with genotype CYP3A5*1/1* and CYP3A5*1/*3 showed greater survival than those patients with CYP3A5*3/*3 genotype, but, in contrast with the previous cited study, no relationship between the dose adjustment was found.

Although it may seem logical that for transplant patients with the slow metabolizing isoforms of cyclosporine the prescribed dose should be higher, the different clinical studies show some controversy regarding the doses that must be prescribed according to the genotype. Although some studies have shown that the dose should be higher for individuals homozygous for the CYP3A5 * 3 isoform, other studies do not observe this relationship and even propose a higher dose of cyclosporin for those patients who are rapid metabolizers. In this context, dose adjustment is performed by monitoring the patient to observe the development of side effects. Neverthless, there is a wide consensus in the fact that in the fast (normal) metabolizers the survival after the transplant is greater.

Although the CYP3A5*3 allele (named with the code rs776746 in clinical data bases) has been to the date the most studied isoform of cytochromes affecting the cyclosporine metabolism and effectiveness, there are several significative studies regarding other isoforms of CYP3A4/CYP3A5.

A recent study on the effect of CYP3A4*22 allele (named with the code rs35599367 in clinical data bases) on 172 renal transplant caucasian patients treated with cyclosporine as immunosuppresant found that the *22 allele was associated with a higher risk of delayed graft function compared with *1 homozygotes. The molecular reason of this clinical evidence is the fact that the CYP3A4*22 isoforms is a slow metabolizer of cyclosporine compared with the wild type isoform.

Summarizing it can be established that the genotypes CYP3A5*1/*1, CYP3A5*1/*3, CYP3A4*1/*1 and CYP3A4*1/*22 are normal (rapid) metabolizers of cyclosporine and have a lower rejection to the transplantation and therefore a greater survival while the genotypes CYP3A5*3/*3 and CYP3A4*22/*22 are slow metabolizers of cyclosporine and present more problems regarding the organ rejection.

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