We, like others, have shown a weak correlation between drug blood levels and clinical outcome and immune response. We have recently established that in contrast to blood levels, drug lymphocyte levels exhibit a strong association with therapeutic efficacy. This discordance is mainly related to the weak association between drug blood level and target cell content as we have reported recently. It explains the intra and inter-individual variability in therapeutic response. These variations are mainly related to both genetic and environmental parameters such as age, gender, body mass index, organ function, food, drugs interaction and availability of extra target cell binding sites. These factors seem to influence all the steps involved in the mode of action of any immunosuppressive agent, including drug absorption, metabolism, elimination, transport, extra target cell sites as well as target cell receptor expression and its binding affinity in addition to specific enzyme baseline activity. Therefore, the cellular fraction of a drug at a fixed dose is the result of the integration of out-fluxing and in-fluxing forces that are affected by both genetic and environmental parameters. Any redistribution of the drug between the different binding sites will ultimately affect its intra-cellular bioavailability and hence its bioactivity without any change in its extra-cellular bioavailability currently determined by plasma or whole blood pharmacokinetic measurements. Monitoring immunosuppression therapy at the site of action appears to be not only more clinically and immunologically relevant than whole blood or plasma level measurements since it measures the free fraction of the drug at it's effector site, but it also allows the bypass of all potential complex extra-cellular interferences with bioactivity. It is truly comparable to pharmacodynamic monitoring since the intra-cellular content of a drug strongly correlates with its biological effect. It is cost-effective and easily applicable in clinical practice and could be used for all immunosuppressive drugs. It should offer a new alternative for immunosuppressive therapy monitoring and tailoring and hence individualisation, since it allows maximal reduction in adverse side effects through dose reduction while maintaining an optimal level of immunosuppression.

Keywords: rats, laser cordectomy, Environmental parameters