Drug Disposition in the Ruminoreticulum
Morphologic and functional characteristics of the ruminoreticulum that make it suitable for fermentative digestion of plant material also affect the activity, distribution, and absorption of many drugs, particularly when given PO. The anaerobic and reductive environment of the ruminoreticulum and the presence of many microbial enzymes result in inactivation of drugs such as trimethoprim and cardiac glycosides. Slow and inefficient mixing of drugs in the large volume of the ruminoreticular fluid delays attainment of uniform concentrations throughout the multiphasic ingesta and retards absorption from the ruminoreticulum. Absorption is also affected by the polarity and ionization status of the drug, which is determined by the pKa of the drug and the pH of the ruminoreticular fluid. The latter depends on the diet and the relative contributions of alkaline saliva and acidic ruminoreticular fluid. Aside from the many effects that the ruminoreticular environment can have on the activity and disposition of drugs, the drugs themselves may have unintended effects on ruminoreticular function. In particular, broad-spectrum antibacterial agents and antiprotozoal agents can disrupt the normal balance of microflora in the ruminoreticulum.
These factors affecting the activity and disposition of drugs in the ruminoreticulum, together with the possible effects of drugs on ruminoreticular function, complicate oral administration of drugs to ruminants. In young animals, these undesirable effects can be avoided by making use of the esophageal groove reflex. This reflex, which is elicited by receptors in the mouth and pharynx, is well developed in suckling neonates but becomes less reliable in older animals. After ~24 mo in cattle and ~18 mo in sheep, provoked reticular groove closure is often irregular, incomplete, or absent.
Ruminoreticular morphology and function has less influence on drug disposition in neonatal ruminants than in adults. At birth, the forestomachs are underdeveloped, and the newborn ruminant is essentially monogastric. Drugs that are usually destroyed in the ruminoreticulum of adults (eg, trimethoprim) may be well absorbed during the first 2–3 wk of life. This developmental pattern depends on the period between birth and initiation of a roughage diet and exposure to microbes in the environment.