for esophageal smooth muscle. In addition, the oesophagus relaxes under the
influence of oxytocic substances and this complicates prediction of the overall
response of the esophagus in different domestic species. Horses are prone to
choke, a condition in which the esophagus is blocked in its distal segment where
the muscles are smooth, so that oxytocin has been recommended in cases of
choking to relax the distal portion of esophagus (Wooldridge et al. 2002 ).
Major differences exist between monogastric species in the gross anatomy and
structure of the stomach. An overview of interspecies differences in gastrointestinal
physiology with special emphasis on monogastric species has recently been
provided by Martinez et al. ( 2002 ) and a review on companion animals and dosage
forms has been given by Sutton ( 2004 ). In monogastric species, the stomach plays
an important role in the disintegration and dissolution of drug formulations and
gastric emptying, with the pylorus acting as a sieving gate leading into the duode-
num. This is the most important physiological factor controlling the rate of access
of a drug to its site of absorption in the proximal part of the gut.
In ruminants, the reticulo-rumen (RR) has a profound influence on the fate of all
drugs due to its large capacity (225L in adult cattle), which leads to dilution and
affects the residence time of orally administered drugs. In addition, the microflora
of the rumen can inactivate drugs by metabolic or chemical reactions.
The rumen wall is keratinised and not well designed to absorb drugs except for
some weak acids such as sulfonamides and salicylic acid (Baggot 1977 ). Con-
versely, the RR fluid, being both very large and acidic (from pH 5.5 to 6.5), can be a
trapping compartment for circulating weak bases and thus influence their systemic
disposition through the classical Henderson–Hasselbalch mechanism. As in mono-
gastric species, the main site of drug absorption in ruminants is the proximal part of
the gut requiring that a drug transits from the rumen through the omasum and
abomasum and the pylorus. Between the reticulo-rumen and the omasum, the
reticulo-omasal orifice (ROO) has a sieving function that can be viewed as the
“pylorus” of the reticulo-rumen. It allows only the passage of small and dense
particles and of solution. When a drug is released from its pharmaceutical form it
may be either in solution in the liquid phase of the ruminal content or be bound to
the ruminal contents such as cellulose. When the drug is in solution, the transit of
the ruminal liquid phase becomes the limiting factor with a relatively slow turnover
rate in the range of 6–15 h. This explains why drugs having a very short half-life by
the IV route, such as salicylic acid (1 h), may nevertheless give sustained plasma
concentrations in ruminants when administered by the oral route, because it is the
rate of transit to the duodenum that controls the overall rate of the systemic
availability (flip-flop phenomenon). The improved bioavailability of several benzi-
midazole anthelmintics, such as fenbendazole, oxfendazole, and albendazole, when
directly deposited in the rumen is probably due to slow transit from the reticulo-
rumen to the abomasum allowing a prolonged duration for drug absorption in the
more distal part of the digestive tract because there is evidence of saturability of
benzimidazole absorption (Sangster et al. 1991 ). If a drug is strongly bound to
cellulose, the transit to the distal part of the gut will be associated with that of small
Species Differences in Pharmacokinetics and Pharmacodynamics 35