Original research

September and October, 1998

Pharmacokinetic modeling of in-feed tetracyclines in pigs using a meta-analytic compartmental approach

Jerome R.E. del Castillo, DMV, IPSAV, MSc; Johanne Elsener, DMV; Guy P. Martineau, DMV, DESS

del Castillo JRE, Elsener J, Martineau GP. Pharmacokinetic modeling of in-feed tetracyclines in pigs using a meta-analytic compartmental approach. Swine Health Prod. 1998;6(5):189-202.

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ABSORPTION: The process by which unchanged drug proceeds from the site of administration to the site of measurement within the body (e.g., blood). Some of the drug may remain in the administration site (i.e., adsorbed by feed particles; or in insoluble salts when injected intramuscularly or subcutaneously) or may be metabolized during transit between the administration site and the measurement site (i.e., destroyed by the liver or other tissues that possess the appropriate enzymes). Drug absorption is described with two pharmacokinetic parameters: BIOAVAILABILITY and ABSORPTION RATE CONSTANT.

ABSORPTION RATE CONSTANT: The rate at which the drug is transferred from the administration site to the site of measurement. In other words, it is the proportion of the dose that proceeds to blood per unit of time. That is, ka=0.75 h-1 means that 75% of the dose remaining in the administration site is absorbed per hour of time.

BIOAVAILABILITY: The rate and extent of drug absorption. In other words, it is the fraction of the dose that will reach the site of measurement after extravascular administration, compared to a standard route. When the standard route is an intravascular administration, the result is called ABSOLUTE BIOAVAILABILITY. When the standard route is also extravascular, the result is called RELATIVE BIOAVAILABILITY.

BIOEQUIVALENCE: When two different products possess equal pharmacokinetic properties, so they can be used interchangeably. Tetracyclines are erroneously considered to be " bioequivalent ," and many practitioners switch from one to another according to economic criteria.

CLEARANCE: The loss of drug by the blood when passing across an organ of elimination. It is also defined as the volume of a body fluid (e.g., plasma) that is totally purified of drug molecules per unit of time.

DISTRIBUTION: The process of reversible transfer of a drug to and from the measurement site. Once in blood, the drug proceeds to tissues so an equilibrium between blood and tissues is achieved. Distribution is affected by the blood supply to the tissue, the ability of the drug to cross tissue membranes, binding of the drug within blood and tissues, and partitioning into fat. DISTRIBUTION VOLUME is a pharmacokinetic parameter describing the distribution of drug within the body.

ELIMINATION: The irreversible loss of drug from the site of measurement. Some drugs will be metabolized when passing through the liver or some other tissue that has the required set of enzymes. Others will be directly eliminated when passing through the kidney or other excretion tissues. CLEARANCE, ELIMINATION RATE CONSTANT, and ELIMINATION HALF-LIFE are pharmacokinetic parameters describing the elimination of drugs.

ELIMINATION RATE CONSTANT: The rate at which a drug disappears from the site of measurement. In other words, it is the proportion of the dose that proceeds outside the blood per unit of time (e.g., k=0.13 h-1 means that 13% of the dose remaining in the site of measurement is eliminated per hour of time).

ELIMINATION HALF-LIFE: The amount of time required to eliminate half of the amount of drug remaining in the body.

EXCRETION: The irreversible loss of chemically unchanged drug (through target or nontarget tissues. This is one type of elimination.

KINETICS OF BACTERICIDAL ACTIVITY: Drugs are historically divided into bactericidals and bacteriostatics. This classification does not take into account the effect of drug concentration over time. When studying the effect of antibiotics on bacteria over time, it is apparent that drugs behave in two different ways that are not reflected by the old classificatory system. With drugs possessing concentration-dependent bactericidal activity (Figure 2), the number of bacterial cells that die is direct function of how much the drug concentration exceeds the MIC (e.g., the more drug you add, the more cells die and the faster they die). Fluoroquinolones and some aminoglycosides, as well as metronidazole with anaerobic bacteria, show this type of bactericidal activity. With drugs possessing time-dependent bactericidal activity, the number of cells that die reaches a maximum (e.g., no further addition of drug will increase bacterial death or death rate). Cephalosporins, macrolides, and other bacteriostatic protein inhibitors show this type of activity. Many antibiotics exhibit either types of bactericidal activity, depending on the Gram type of the test bacteria (e.g., concentration-dependent with Gram-positive organisms and time-dependent with Gram-negative organisms).

LINEAR PHARMACOKINETICS: When pharmacokinetic properties of a drug remain constant throughout a wide range of dosages. Concentrations at the site of measurement are always directly related to dose, both for single and multiple doses.

METABOLISM: The conversion of one chemical species to another. Metabolism may have an effect on the biological activity of a drug (i.e., metabolism can decrease, increase, or have no effect on the activity of drugs). There are minor reactions (known as Phase I metabolism) and major reactions (Phase II metabolism) that increase the ability of the body to eliminate the drug. Enzymes such as the cytochrome P450 isoenzymes are responsible for the metabolism of drugs.

PHARMACOKINETICS: the study of the evolution of drug absorption and disposition by the living body over time and the use of mathematics to describe and predict the whole process. Drug disposition is characterized by two events that occur simultaneously: DISTRIBUTION through the body and ELIMINATION by means of METABOLISM or EXCRETION.

PHARMACODYNAMICS: The study of the relationship between drug concentrations at the site of action and drug effects, factors influencing this relationship, and the use of mathematics for the description of the process. Models that can both describe the observations and offer some insight into the underlying biological process are usually preferred. Determining the POST-ANTIBIOTIC EFFECT, the POST-ANTIBIOTIC LEUKOCYTE ENHANCEMENT EFFECT, and the KINETICS OF BACTERICIDAL ACTIVITY are different ways to study the pharmacodynamics of antimicrobial drugs. The minimum inhibitory concentration, the minimum bactericidal concentration, and antimicrobial sensitivity testing do not provide any information on the time course of antimicrobial activity or the persistent effects of antimicrobial agents, and thus are not considered to be pharmacodynamic parameters.

POST-ANTIBIOTIC EFFECT: The persistent suppression of bacterial growth after exposure to an antimicrobial. It can be conceived of as the time it takes for an organism to recover from the effects of exposure to an antimicrobial. The post-antibiotic effect has been observed both under in vitro and in vivo conditions. The span of the post-antibiotic effect is affected both by the concentration and the duration of exposure of bacteria to drug. SubMIC concentrations of antibiotics are known to slow growth, produce morphological changes, and prolong the duration of the in vivo post-antibiotic effect produced by supraMIC concentrations.

POST-ANTIBIOTIC LEUKOCYTE ENHANCEMENT EFFECT: The increase in susceptibilty of bacteria in the post-antibiotic phase to phagocytosis or intracellular killing by leukocytes. The inhibition of bacterial repair mechanisms or antiphagocytic substance production by antibiotics is thought to be the cause of this phenomenon.

PRINCIPLE OF SUPERPOSITION: For drugs that possess linear pharmacokinetics, all kinetic profiles corrected for the administered dose can always be superimposed--i.e., added to the concentration of the drug already available in plasma at the time of the next administration. When kinetic profiles fail to superimpose, the drug possesses nonlinear pharmacokinetics for either dose (e.g., saturation of transport across membranes, protein binding, etc) or time (e.g., induction/inhibition of metabolism).

VOLUME OF DISTRIBUTION: The apparent volume in which a drug distributes in the body at equilibrium of drug between blood and tissue. It is a direct measure of the extent of distribution, but it rarely corresponds to a real volume (e.g., plasma; extracellular water; total body water).