Interleukins. Clinical pharmacokinetics and practical implications.

Abstract

Interleukins and tumour necrosis factor (TNF) are a complex group of proteins and glycoproteins able to exert pleiotropic effects with respect to a number of different target cells. In physiological conditions, they are induced and released in basal amounts only in restricted microenvironments where they have paracrine activity. Any small amounts reaching the circulation do not disturb homoeostasis. During therapy, particularly when these cytokines are administered via conventional routes, it has become apparent that their presence in nonphysiological plasma concentrations and their unselective action cause toxic effects with small benefits. The pharmacokinetics of interleukins-1, -2, -3 and -6 and TNF have been evaluated, and their disappearance from plasma after intravenous administration is very rapid (i.e. the distribution half-life is measured in minutes; the elimination half-life is several hours). The efficiency of catabolic pathways such as renal filtration and/or liver uptake is interpreted as a salutary mechanism for extracting proteins that should not be in the circulation. However, because these cytokines are very potent immunomodulatory agents there is a need to improve their therapeutic index, and to this end a number of possible formulations and routes of administration are now available and may eventually be of practical use.