In contrast with interspecies differences in PK, examples of PD interspecies
differences are less numerous and not so well documented. One such example is
that of mydriatic drugs, with the parasympatholytic agent atropine being mydriatic
in mammals but not in birds. In birds, the iris and ciliary muscles are composed
mainly of striated muscle fibres with an associated nicotinic cholinergic neuromus-
cular junction (Glasser et al. 1995 ; Pilar et al. 1987 ). These striated muscle fibres
facilitate a rapid pupillary and accommodation response and this is likely to be an
adaptation to the visual requirement of flight. In birds, atropine, a muscarinic
receptor antagonist has no mydriatic effect, whereas neuromuscular blockers
such as d-tubocurarine dilate pupils. In mammals, the iris is composed of smooth
muscle, and muscarinic agonists act on receptors of the M3 subtype to cause pupil
dilatation.
For drugs affecting reproduction, very large interspecies differences exist and
these are easily explained by basic mechanisms of reproductive physiology. For
example, the annual pattern of the reproductive cycle is seasonal in small rumi-
nants, but not in cattle. It was established that seasonality is under photoperiodic
control through the secretion of melatonin by the pineal gland during the dark phase
of the nycthemere. Thus, melatonin was rationally developed as a drug for use in
sheep and goats to hasten the onset of the breeding season and to increase prolifi-
cacy. The estrus cycle is qualitatively similar in cattle, sheep, goats, and horses but
its overall duration and the relative duration of the luteal and follicular phases have
led to specific recommendations regarding the rational use of different hormones
used to control the estrus cycle and also to the design and development of controlled
release vaginal and non-vaginal systems such as subcutaneous implant containing
GnRH or ear implants releasing steroids (for a review see Rathbone and Witchey-
Lakshmanan 2000 ).
Prostaglandin analogues are used to induce farrowing (parturition) within a time
limit of 3 days, because in the pig, progesterone of ovarian origin (corpus luteum) is
necessary to maintain a pregnancy until term. This is not the case in sheep where
progesterone of placental origin becomes sufficient to maintain pregnancy after a
delay of about 2 months. This explains why luteolytic substances that suppress
progesterone production by the corpus luteum are abortive in sows throughout
pregnancy but not beyond 55 days in sheep.
In ruminant species, cortisol of foetal origin plays a pivotal role in the
initiation of parturition in the last days of pregnancy and synthetic fluorinated
corticoids (dexamethasone, flumethasone, betamethasone) are also able to trig-
ger parturition within the 2 last weeks of pregnancy in cows providing that the
foetus is alive, while the same fluorinated corticosteroids are not effective in
horses, pigs, and dogs. The size of the prostate gland is species-specific, and in
domestic species it is only in dogs that the prostate attains the same degree of
compactness as in man; in other species including bulls, sheep, goats and
pigs the prostate is rudimentary. In addition, the prostate (even rudimentary)
atrophies in the absence of circulating testosterone. These differences explain
why prostatitis is an infectious condition that oftenaffects entire male dogs
that is difficult to treat because of a prostate barrier due to the tight junctions
28 P.-L. Toutain et al.