The key aspects of the pharmacokinetics of transdermal delivery system
s including time lag, steady-state plasma levels and decline phase are
illustrated in this review. The 7 currently marketed transdermal syst
ems [nitroglycerin (glyceryl trinitrate), estradiol, clonidine, fentan
yl, nicotine, scopolamine (hyoscine) and estradiol/norethisterone acet
ate] are discussed, as are systems in development. Single-dose absolut
e bioavailability studies characterise the period of onset, the steady
-state plateau and the declining phase, and typify transdermal deliver
y. More complex temporal profiles result from interactions with enhanc
ers or removal of the system before steady-state conditions are achiev
ed. Clinically these systems are used to achieve multiple peak serum e
stradiol concentrations after application of transdermal estradiol, an
d an initial peak systemic concentration of testosterone after applica
tion of transdermal testosterone. Multiple-dose, dose proportionality
and skin site bioequivalence studies are needed for the full pharmacok
inetic characterisation of a transdermal delivery system. The relation
ship of system design to variability is discussed. Although the data a
re limited, population factors, cutaneous metabolism and tolerance all
appear to influence the disposition of drugs administered transdermal
ly. For example, the route of delivery influences which nitroglycerin
metabolite predominates. Futhermore, as a result of tolerance to nitra
tes, a transdermal delivery system must be removed for 8 to 12 hours f
or optimal effect. Therefore, transdermal delivery systems, designed o
n the basis of pharmacokinetic principles and concentration-effect rel
ationships, have the potential to provide optimal therapy for the trea
tment of some conditions.