Since their introduction circa 35 years ago, calcineurin-inhibitors (CNI) have become
the cornerstone of immunosuppressive therapy in solid organ transplantation. However,
CNI's possess a narrow therapeutic index with potential severe consequences of drug
under- or overexposure. This demands a meticulous policy of Therapeutic Drug Monitoring
(TDM) to optimize outcome. In clinical practice optimal dosing is difficult to achieve
due to important inter- and intraindividual variation in CNI pharmacokinetics. A complex
and often interdependent set of factors appears relevant in determining drug exposure.
These include recipient characteristics such as age, race, body composition, organ
function, and food intake, but also graft-related characteristics such as: size, donor-age,
and time after transplantation can be important. Fundamental (in vitro) and clinical
studies have pointed out the intrinsic relation between the aforementioned variables
and the functional capacity of enzymes and transporters involved in CNI metabolism,
primarily located in intestine, liver and kidney. Commonly occurring polymorphisms
in genes responsible for CNI metabolism (CYP3A4, CYP3A5, CYP3A7, PXR, POR, ABCB1 (P-gp)
and possibly UGT) are able to explain an important part of interindividual variability.
In particular, a highly prevalent SNP in CYP3A5 has proven to be an important determinant
of CNI dose requirements and drug-dose-interactions. In addition, a discrepancy in
genotype between graft and receptor has to be taken into account. Furthermore, common
phenomena in solid organ transplantation such as inflammation, ischemia- reperfusion
injury, graft function, co-medication, altered food intake and intestinal motility
can have a differential effect on the expression enzymes and transporters involved
in CNI metabolism. Notwithstanding the built-up knowledge, predicting individual CNI
pharmacokinetics and dose requirements on the basis of current clinical and experimental
data remains a challenge.