Advances in molecular biology and recombinant DNA technology have led
to the development of cytokines as therapeutic agents for a variety of
disease states. The pharmacokinetic analysis of cytokines involves th
e understanding of analytical methods capable of detecting these agent
s in biological fluids and recognition of several factors which may ha
ve an impact on the cytokine concentration-time curves. Enzyme-linked
immunosorbent assays (ELISA) have become the most common method of det
ection and commercial kits are available for a wide variety of cytokin
es. Monoclonal antibody products are sensitive, have minimal crossreac
tivity and are relatively inexpensive when compared with high performa
nce liquid chromatography (HPLC). However, the primary limitation of t
hese assays is their inability to measure biologically active protein.
Conversely, bioassays do measure a biological event (i.e. proliferati
on or cytotoxicity) but are generally not used for cytokine analysis b
ecause of their high cost, long assay completion time, lack of specifi
city, poor sensitivity and influence of environmental conditions on th
e outcome. The pharmacokinetic profile of recombinant cytokines is inf
luenced by a number of variables: endogenous production, circulating s
oluble receptors and cell-associated receptors, immunocompetence and a
ntibody production against the cytokine all may influence the disposit
ion of the agent. Thus, pharmacokinetic modelling of cytokines may inv
olve complex models capable of characterising these nonlinear processe
s and resulting effects. The route of administration is an important v
ariable since cytokines administered by subcutaneous injection may be
partially metabolised by proteases present in the subcutaneous tissue.
Other methods to simplify cytokine delivery are being actively invest
igated and include formulations for inhalation, topical and oral admin
istration. A variety of cytokines (including interferon-alpha, interle
ukin-6 and tumour necrosis factor) are capable of inhibiting cytochrom
e P450 hepatic enzymes and, therefore, possess the potential to cause
drug-cytokine interactions. Inhibition has been demonstrated in severa
l in vitro systems and animal models, although clinical data are curre
ntly limited. An increased understanding of the many factors which can
alter the analysis and pharmacokinetics of cytokines is essential to
the design of optimal dosage regimens.