Small Animal Clinical Pharmacology - CYF MEDICAL DISTRIBUTION

CHAPTER 1 PRINCIPLES OF CLINICAL PHARMACOLOGY
● Barrier to absorptive surfaces. Food may impose a
physical barrier to the dissemination of drugs to
mucosal absorptive surfaces. In addition, some food
constituents (particularly fiber) can be a site of drug
adsorption, effectively reducing the quantity of drug
available for absorption.
● Pharmacologically active food constituents. While
not a usual component of the diet of dogs and cats,
in humans the ingestion of Seville oranges, limes
or grapefruit juice (which all contain biologically
active polyphenolic furanocoumarins) has been
reported to inhibit certain cytochrome P450 isoenzymes
(particularly CYP3A), leading to increased
bioavailability of a number of drugs that otherwise
would have been metabolized. Inhibition of CYP has
also been reported in humans consuming garlic
extracts or St John’s wort.
The magnitude of a food–drug interaction is dependent
on the following factors.
● The physicochemical properties of the drug
– The main considerations include the pKa and
chemical lability of the drug.
– Nonionized forms of drugs are most readily
absorbed and the pH of the milieu in which the
drug is absorbed will determine the relative concentrations
of ionized and nonionized drug.
– Acid-labile drugs may benefit (though unpredictably)
from coadministration with food, as
gastric pH is buffered and elevated to a variable
extent.
● Formulation
– Egress from the stomach is quickest for solutions,
followed by suspensions, pastes, tablets and
capsules.
– It has been observed that particles of diameter up
to 1.6 mm empty more rapidly than the meal,
while particles larger than 2.4 mm empty more
slowly.
– The protective barriers provided by enteric-coated
tablets may be breached and protection from
gastric acid reduced if the dosage form resides for
protracted periods in the stomach.
– Formulations with a density less than unity may
have increased residence in the stomach due to
buoyancy effects. Experimentally, advantage has
been taken of this phenomenon in the design of
sustained-release formulations.
● Type and size of meal
– Liquid and low-viscosity meals are associated
with rapid gastric emptying and may lead to
increased or decreased bioavailability of coadministered
drugs, depending on the time necessary
for disintegration and dissolution of dosage
forms.
– High-fat meals are followed by increased concentrations
of circulating free fatty acids, which
bind to albumin and limit the number of binding
sites available for acidic drugs. This can lead to
increased free drug and more rapid clearance.
Notably, fasting is also associated with increased
concentrations of free fatty acids from the mobilization
of endogenous depots and can lead to the
same effect on drugs.
– In humans, diets high in protein and low in carbohydrate
have been associated with increased
hepatic mixed function oxidase activity, which
led to more rapid clearance of theophylline and
propranolol.
– The bioavailability of a number of drugs (especially
the fluoroquinolones and tetracyclines;
doxycycline is an exception) is adversely affected
by the presence of divalent and trivalent cations,
as may be present in dairy products (Ca 2+ ) and
antacids (Mg 2+ and Al 3+ ). Insoluble complexes are
formed, resulting in reduced absorption. Dietary
milk can elevate gastric pH and accelerate the
dissolution of enteric-coated tablets, leading to
drug release and possible gastric irritation or drug
degradation.
– A number of studies in dogs have demonstrated
a more marked effect on drug availability
of dry food than semi-moist canned food, presumably
because of a more delayed gastric
emptying.
● Time interval and sequence between eating and drug
administration
– While the optimum fasting period will depend on
the animal, the drug and the meal, for those drugs
that may be adversely affected by feeding it is
generally recommended that 1–2 hours should
elapse between feeding (either before or after) and
drug administration.
– A possible exception is that a greater period may
be necessary after feeding when a dry ration is
consumed.
Drug interactions
A drug interaction occurs when the effect of one drug
is changed by the presence of another drug. The interaction
can have positive (e.g. the synergism of coad
ministered amoxicillin and clavulanic acid) or harmful
consequences (as may be associated with the interaction
of potassium-depleting diuretics and digoxin). Many
possible interactions have been described in both medical
and veterinary practice, but a caution has been issued
that the data are widely variable in quality and reliability.
While some interactions have been critically evaluated
under controlled conditions, others ‘are no more
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