CAL 3
Comparative Veterinary Pharmacokinetics
1. Introduction
In veterinary clinical practice, the sensitivity of a given animal species to a drug varies due to pharmacodynamic and pharmacokinetic differences.
In humans, individual differences are crucial, while in veterinary medicine, interspecies and inter-breed differences are more significant.
Pharmacokinetics is defined as the behavior of a drug in the body, covering aspects such as absorption, distribution, metabolism, and elimination (ADME).
For a drug to have a systemic effect, it needs to be absorbed and distributed to therapeutic concentration at its site of action.
If the target site is the gastrointestinal (GI) tract, absorption is unnecessary (in cases of oral administration).
There are significant variations in absorption, distribution, metabolism, and elimination processes across different animal species.
Due to pronounced interspecies variations, it is inappropriate to extrapolate pharmacokinetic data from humans or other animals, leading to hazardous consequences for certain drugs.
Nonetheless, the lack of pharmacokinetic data often necessitates using extrapolated human dosages empirically.
This chapter focuses on variations in the ADME process between different animal species, breeds, and ages.
2. Administration Routes in Veterinary Practice
Administration routes in veterinary medicine largely mirror those in human medicine, with minor distinctions.
Major routes of drug administration include:
Intravenous (IV): Fastest drug action; no absorption necessary.
IV bolus administration results in high plasma levels and rapid action.
Continuous IV infusion allows for controlled effects through steady-state plasma concentration.
Commonly used for anesthetics like propofol but also carries toxicity risks due to rapid entry into circulation.
Intramuscular (IM) and Subcutaneous (SC): Frequent in ruminants, swine, horses, dogs, cats, and rabbits.
Absorption rates are influenced by the administration route, vascularity of the site, drug concentration, and ionization.
Suprascapular IM injection leads to quicker absorption compared to other sites like the gluteal muscles.
Peak plasma concentrations typically achieved 20-40 minutes post-administration.
Oral (PO): Most common route; especially for food-producing animals.
Drugs can be administered via drinking water or mixed into feed in poultry and swine.
Various dosage forms include boluses, drenches, oral gels, pastes, tablets, capsules, solutions, and suspensions.
Topical: Raises pharmacokinetic issues; discussed in detail in the chapter on drug absorption.
Intramammary: Vital for treating and preventing mastitis in cattle.
Inhalational: Another route applicable to veterinary practice.
3. Absorption of Drugs
Absorption is necessary for drugs administered via any route except IV; the extent of absorption indicates bioavailability.
Bioavailability is defined as the ratio of the area under the curve (AUC) of the drug after extravascular vs. intravenous administration:
Different types of bioavailability exist, including oral, IM, SC, and topical.
Greatest interspecies variations occur following oral administration; hence it is a focal point in this section.
Key factors affecting the extent and rate of absorption are:
Lipophilicity: Higher lipophilicity typically increases absorption.
Molecular weight: Influences ease of passage across membranes.
Degree of ionization: Affects solubility at the site of administration.
Weak acids (e.g., NSAIDs) are more non-ionized in the acidic stomach environment improving their absorption in the proximal GI tract.
These acids exhibit lower Tmax (time to reach maximum plasma concentration).
Weak bases, being ionized in the stomach, usually have higher Tmax values.
First pass effect can significantly modify oral bioavailability as many drugs like lidocaine and morphine are inactivated in the liver upon first exposure.
Parenteral or rectal administration routes can bypass the first pass metabolism.
Pharmaceutical formulations can alter absorption rates, delaying or prolonging effects.
Examples include modified-release tablets and depot injections.
Certain physical interactions with food can impede absorption (e.g., tetracyclines forming insoluble complexes with calcium).
Diseases causing increased gastrointestinal motility can lead to decreased absorption efficacy.
Example: In canine or feline parvovirosis leading to increased absorption rates of certain previously unabsorbed substances.
3.1 Differences in Oral and Parenteral Absorption among Animal Species
Understanding monogastric versus ruminant, herbivore, omnivore, and carnivore digestive systems is vital for comparative pharmacokinetics.
The GI tract length and volume in ruminants (like cows) slow down drug absorption significantly in comparison to non-ruminant species (like dogs).
For example, benzimidazole anthelminthics (e.g., albendazole) can provide prolonged action in ruminants, while dogs and cats typically require multiple doses.
The oral bioavailability of amoxicillin varies:
Horses: 5%
Swine: 28-33%
Poultry: 59-68%
Dogs & Cats: 60-80%
Notably, some antibiotics show variable efficacy due to decreased absorption in specific species unless formulated properly.
For ruminants, due to the extensive ruminal fluid volume, drug efficacy may be diminished unless specifically formulated for sustained release.
3.2 Percutaneous Absorption after Topical Administration
Absorption occurs in three phases:
The drug must be dissolved.
It must penetrate the stratum corneum and epithelial layer.
It ultimately needs to enter the bloodstream.
Lipophilicity is a critical factor for effective percutaneous absorption.
Certain substances, including some ectoparasiticides and glucocorticoids, have high percutaneous absorption rates but are influenced by skin thickness and integrity.
Inflammation or skin damage can enhance absorption, previously noted in feline reactions to certain spot-on products containing methyl- or ethyl-based derivatives.
3.3 Intranasal Absorption
Intranasal drug application is less common but growing in veterinary practice; advantageous due to avoiding first-pass metabolism.
Example: Oxytocin for inducing labor in swine.
Other drugs like diazepam, used as an anticonvulsant, show promising nasal bioavailability of 41–42% in dogs, providing crucial alternatives for status epilepticus.
3.4 Intramammary Absorption
Commonly used for antibiotics and anti-inflammatory drugs in dairy cattle for treating mastitis.
Conditions promoting inflammation enhance absorption rates in mammary tissues compared to healthy states.
4. Drug Distribution
Post-absorption, drugs are distributed throughout the body, which varies based on tissue access and blood flow rates.
Factors affecting this distribution include lipophilicity, molecular weight, ionization, and local blood flow rates.
The volume of distribution (Vd) quantifies drug distribution in plasma: where:
$A(t)$ = amount of drug in the body
$C_p$ = plasma concentration
A high $V_d$ indicates extensive distribution beyond plasma concentrations, as seen with highly lipophilic drugs that accumulate significantly in specific tissues.
5. Drug Metabolism
Metabolism processes involve modifying the drug to enhance excretion potential; primarily through biotransformation.
Biotransformation occurs in two phases:
Phase I (non-synthetic): Involves chemical alterations that prepare the drug for conjugation.
Phase II (synthetic): Conjugation with polar substances that enhances water solubility.
Significant species variations occur in drug metabolism, particularly in different Phase II conjugation pathways.
6. Drug Excretion
Elimination is achieved through metabolism and primary excretion pathways (mostly renal).
Elimination kinetics typically follow first-order processes but can transition to zero-order when excretion processes become saturated complicating the medication regimens especially in animals susceptible to toxicity.
7. Acknowledgement
Expresses gratitude to Dr. József Lehel and Dr. Melinda Donka-Jerzsele for their expert guidance throughout the chapter.