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Pharmacokinetics
Penethamate hydriodide is a diethylaminoethyl ester of penicillin
which, unlike salts of penicillin, is unionised and so exists in a
neutral state. It is only weakly water soluble (1% at 20°C) and so
forms a suspension in an aqueous environment. After intramuscular
administration, Mamyzin is rapidly absorbed from the site of injection
and on entering the blood, penethamate partially dissociates by
hydrolysis into penicillin G and diethylaminoethanol (fig 1). At the
blood pH (7.2), equilibrium is established where 191.8% of the active
drug is present in its hydrolysed form (penicillin G) with the
remainder persisting as penethamate. As penethamate leaves the
circulation due to its neutral and lipophilic properties and its high
affinity to milk (see opposite), this equilibrium is maintained by
re-association of penicillin G and diethylaminoethanol until excretion
is complete.
Pharmacokinetics in milk
Following administration of Mamyzin, the un-dissociated penethamate
circulates in the blood (pH ± 7.2) in a non-ionised form. This easily
passes over the milk-blood barrier due to the pH gradient present
between milk (pH 6.6-6.8) and plasma (pH 7.2) and its weakly basic
state (pKa = 8.4). This is further facilitated by its highly lipophylic
properties which ease its passage across the lipo-proteineic blood-milk
barrier5.
Penethamate starts to dissociate as it passes over the blood-milk
barrier and this continues during diffusion of the drug through the
udder, releasing increasing quantities of penicillin G. The penicillin
G is rapidly ionised in the udder (pKa = 2.8) so limiting its return to
the circulation. It therefore becomes "trapped" in the udder in
increasing concentrations (fig 2).This is described as "ion trapping".6
The same pH gradient between blood and milk presides in the presence of
mild to moderate udder inflammation such as in cases of sub-clinical
mastitis, thus creating similar pharmacokinetics to those which occur
in the healthy udder. In acute mastitis, although the pH of milk is
nearer that of blood due to a breakdown of the blood-milk barrier,
higher concentrations of penethamate are still to be found in mastitic
milk than in blood due to its lipophilic properties5.
Not only does un-dissociated penethamate rapidly and easily penetrate
the udder whether inflamed or not, but its liposoluble nature gives it
a superior aptitude, compared with beta-lactam antibiotics such as
amoxicillin and aminoglycosides such as streptomycin to diffuse through
the parenchyma of the udder, pass into the milk and penetrate the
lactogenic cells7. It is shown to penetrate the udder eight times faster than penicillin G administered by the intramammary route7.
This diffusion through the udder is supported by the mechanism of "ion
trapping" discussed above and so explains the milk concentration
characteristic of penethamate compared with penicillin G.
After intramuscular injection of Mamyzin in cows, mean maximum
penicillin concentrations are achieved in the udder 5.91 hours after
injection. This is greater than twice the concentration (mean area
under the curve AUC) present in serum4. (fig 3) Pharmacokinetic calculations show that whilst the concentration of penethamate in
mastitic milk from cows with acute disease may be slightly lower than
that in healthy milk and that found in sub clinical disease due to the
change in milk pH, it is maintained for longer. For example, in work
carried out by Ziv7 administration of penethamate at the recommended
dose provided levels of penicillin in the milk above the MIC of a
susceptible pathogen for 24 hours in the milk from cows with acute
mastitis compared with 12 hours in normal milk. This compared with a
reverse relationship for a number of aminoglycoside antibiotics.
Metabolism and excretion
After IM injection, all the penethamate is hydrolised to penicillin G
prior to excretion. 40 to 70% is eliminated unchanged in the urine,
essentially during the first hours after administration. A weak
elimination may also take place via bile. That remaining, which is not
excreted in the milk, is partially metabolised (30-60%) by hydrolysis
of the AY?N-lactam nucleus in the liver to, amongst other derivatives,
penicilloic acid and penicillenic acid, both biologically inactive.
These are eliminated in the urine.
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