Mammary Glands
Pharmacokinetics of the mammary gland
By www.exopol.com
Nov 5, 2002, 10:10am

http://www.exopol.com/in/circulares.in/07.in.html

The efficacy of an antimicrobial compound depends on a number of factors, including the susceptibility of the etiologic agent involved, the chronification of infectious processes (production of exopolysaccharides and of microcolonies in the case of staphylococci: see Circular 3), the type of lesions produced, and the intrinsic characteristics of the compound administered that condition its concentration and persistence within the body (pharmacokinetics).

This circular briefly addresses the pharmacokinetics of the mammary gland, with the aim of contributing to better utilization of antibiotics. The treatment of mastitis can be carried out both via the intramammary route and systemically, depending fundamentally on the severity of the observed symptoms. It is therefore advisable to take into account the pharmacokinetic characteristics of both administration routes, as they will largely determine the dose, frequency and time to action of the therapy.

SYSTEMIC ROUTE

From the pharmacological perspective, the mammary gland is a compartment isolated from the rest of the organism; consequently, the success of treatment adopting the systemic route requires passage of the drug substance from the blood to the milk, though the lipid membranes of the gland — these being similar to the barriers existing in the brain or in the eye. Antimicrobial passage across this barrier is a passive process, i.e., it is dependent upon the concentration gradient of the drug across the barrier — with the added limitation that only lipidic substances are able to cross the barrier. The pharmacokinetic characteristics to be desired in a compound for the parenteral treatment of mastitis can be summarized as follows:

- A low minimum inhibitory concentration, thus indicating good in vitro activity of the antimicrobial against the agent in question. It should be taken into account that in some cases the correlation between antimicrobial activity in vitro and in vivo is limited — a fact that may lead to treatment failure. However, correlation is greater in the case of bacterial resistance, i.e., a germ that is resistant in vitro is likely also to be resistant in vivo.

- A high bioavailability following intramuscular injection, implying that a large proportion of the dose administered via an extravascular route will reach the blood.

- Distribution volume and elimination rate. Figure 1 shows the course of the blood concentration of an antibiotic injected via the intravenous route. Two phases can be observed: an alpha phase, in which diffusion of the drug through the body predominates, and a beta phase, in which drug metabolization and elimination predominate. The latter phase corresponds to a straight line that extends to a point Co (concentration at time zero). This value indicates the theoretical maximum concentration that the drug would reach in blood if diffusion through the tissues were instantaneous following injection. Once this value has been established, it is possible to calculate the distribution volume (Vd), obtained by dividing the dose administered by Co (Vd = dose administered / Co). Vd indicates the greater or lesser distribution capacity of the drug within a given part of the body.

On the other hand, the elimination rate of a compound can be expressed as the half-life (t1/2), or the time required for the concentration of the antimicrobial to decrease to half the initial value. The shorter the half-life, the less time the drug persists in blood and mammary tissue. This parameter is therefore important when determining the dosing regimen. As an example, in the case of treatment during lactation, rapid elimination or clearance of the drug is desirable, in order to allow the release of milk for consumption as soon as possible. In fact, certain products with these characteristics are already available on the market (Excenel; Upjohn), and Pitman-Moore will soon market another.

- Good liposolubility. The passage of the drug substance across the blood-milk barrier takes place by passive diffusion, and is dependent on the drug concentration gradient across the barrier and on the liposolubility of the substance, among other factors. In situations of mastitis the blood-milk barrier is partially ruptured, thus allowing certain scantly liposoluble substances to cross the barrier and thus reach higher concentrations in mammary tissue — thereby facilitating improved therapeutic action.

- Reduced binding to plasma proteins. The antimicrobial molecule can be found in blood either bound to plasma proteins (fundamentally albumin), or in free unbound form. The protein-bound fraction is unable to diffuse across the blood-milk barrier, i.e., drug affinity for plasma proteins conditions the choice of a given compound.

The systemic treatment of mastitis is normally carried out in situations of serious acute infection in which general symptoms are observed.

INTRAMAMMARY ROUTE

The intramammary route is advised for the treatment of moderate clinical mastitis, and should be used in combination with the parenteral route in severe cases.

The pharmacokinetic characteristics of the compound determine its bioavailability, in the same way as in systemic administration. The type of vehicle employed, the size of the active particles, their solubility and other factors are equally important considerations. Part of the antimicrobials administered bind to the plasma proteins, and even to the mammary gland tissue — which acts as a drug reservoir and thus prolongs antimicrobial action. In the treatment of mastitis during lactation, the best antimicrobial choice is a drug of optimal action that is in turn eliminated as quickly as possible (as has been mentioned above), in order to reduce the waiting period for the release of milk production as far as possible.

On the other hand, treatment in drying situations requires the use of substances that act as long as possible upon the mammary tissues. In this sense, the insoluble salts of certain compounds, vehicles in the form of vegetable oils, or microencapsulation are procedures that ensure slower release of the active drug substance.

It is this persistent presence of these products under mammary drying conditions that determines their therapeutic efficacy, for as can be seen in Figure 3, drying is a moment involving a high incidence of new infections.

COMMENTS

In general, the usefulness of antibiograms often centers on determining which antibiotics have been excessively used. As a general rule, the indications should be changed every one or two years to avoid the appearance of resistances.

As has been mentioned above, in vitro susceptibility to a given antibiotic does not necessarily imply that the same drug will be effective in vivo — though in vitro resistance generally does imply in vivo resistance as well.

In many cases, a lack of results with antibiotic treatment in chronic processes is not due to resistance problems but rather to the presence of lesions that protect the bacteria and, according to our investigations, also to the appearance of microcolonies protected by bacterial exopolysaccharides. In fact, it is very common in chronic farms to isolate strains that are susceptible (in vitro) to any treatment.

The in vitro use of discs containing antibiotic combinations usually yields misleading results. In fact, in other species, where resistance is observed with some frequency for all tested antibiotics, a telling observation is that the only discs seen to inhibit bacterial growth are those corresponding to some of these combinations. Moreover, on certain occasions the use of these combinations perceived to be useful for all purposes simply reflects a lack of awareness of the problem being faced.

At present, there is discussion about the possibility of using products in mammary drying administered via the intramuscular route, in view of the high concentrations achieved in mammary tissue in this way. In fact, a number of studies have already been made. Our opinion in any case is that such treatment may be very useful in some situations, such as in sheep that are milked by hand in the absence of troughs.

In this context, intramuscular administration in situations of mammary drying is advantageous when uncertainty exists as to the hygiene of the person applying the therapy.

The figure explains the pharmacokinetics of the mammary gland. After injecting an antibiotic via the intramuscular route, the only useful drug at the mammary level is a substance that does not bind to tissues and passes into the bloodstream (bioavailability). Once in the blood, a fraction binds to the plasma proteins, and the remaining free fraction is the only portion available for action upon the mammary tissues. Moreover, this free fraction of the drug is continuously metabolized and eliminated — a fact that determines very short half-lives (t1/2) of only seconds in the case of some drugs. The drug fraction reaching the mammary tissues must cross the blood-milk barrier (liposolubility), except in those cases where no such barrier exists because of the important inflammation found in the zone. Finally, once the target tissues have been reached, the drug must not bind to the milk proteins if action upon the bacteria is to take occur.

UTILIZATION OF ANTIBIOTIC CANNULAS

In certain places or in some species the use of antibiotic cannulas in mammary drying is not as widespread as it should be, and situations have often developed in which their use has been harmful because cannula insertion has led to the appearance of new infections. The use of such cannulas is simple:

- Cleaning and disinfection of the tip of the teat using iodine or chlorhexidine, with the help of a piece of cotton which should then be discarded.

- Introduction of the cannula, without forcing its advance. This is particularly important in sheep, where cannulas designed for bovine cattle are often used — with the resulting risk of teat sphincter damage.

- Use of different cannulas for each udder. Here again, the common practice of using bovine cannulas in sheep leads to insertion of the same tip into both udders of the animal. This facilitates the development of bilateral infection and should be avoided. It is normally simple to obtain special cannulas for sheep through the commercial distributor.

- In some cases, the absence of milking troughs greatly complicates treatment in mammary drying. In such situations the use of intramuscular treatments may be considered.