"Pharmacokinetics of Antimicrobial Drugs in the Horse"

Abstract

Oral antimicrobial drug therapy in horses is limited by a lack of approved formulations, cost, poor bioavailability and adverse effects. Additionally, little is known about the relationship between plasma concentration and tissue concentrations in horses. Therefore, the purpose of this research was to determine the factors that affect oral absorption and tissue distribution of antimicrobial drugs in the horse. In order to examine this, we performed pharmacokinetic studies using drugs that represent a broad range of physicochemical characteristics as well as drugs that represent different classes based on the Biopharmaceutics Classification System (BCS), a system developed to screen drugs and predict oral drug absorption in humans based on the solubility and permeability characteristics.

Experiments were also performed to study drug concentrations in the tissue — the site of drug action. Interstitial fluid was used to represent unrestricted drug diffusion between capillaries and tissue. The aqueous humor of the eye was chosen to represent areas with physiologically restricted drug penetration. In vitro experiments were performed to determine plasma protein binding, lipophilicity and mucosal permeability of commonly used drugs in the horse.

Four pharmacokinetic studies were completed using voriconazole and orbifloxacin (BCS Class I), cephalexin (BCS Class III) and doxycycline (BCS Class IV). An additional study was done comparing itraconazole capsules (BCS Class II) and itraconazole solution (BCS Class I) to determine the effect of increasing the solubility of a drug on oral absorption. As predicted based on the BCS, voriconazole and orbifloxacin had high bioavailability (135% and 68%, respectively), while cephalexin and doxycycline had low bioavailability (5% and 2.8%, respectively). Itraconazole capsules had a low bioavailability (12%) while the solution had a high bioavailability (64%). These studies confirm our hypothesis that oral drug absorption can be predicted based on the solubility and permeability characteristics of the drug.

Drug concentrations in the interstitial fluid were determined and were found to be highly correlated with the plasma protein binding of the drug. In contrast, drug concentrations in the aqueous humor were found to correlate well with the lipophilicity of the drug.

Our studies next examined methods to confirm the BCS classification based on effective permeability (Peff) of the equine small intestine using an in vitro Ussing chamber model. Fluconazole, metronidazole, marbofloxacin and cephalexin were used in this study because these drugs exhibit high solubility, but they differ in their lipophilicity, molecular weight and oral bioavailability in horses. Good correlations were found between permeability and bioavailability and between permeability and lipophilicity. A strong correlation was also found between the permeability and molecular weight, which may be caused by paracellular transport of drugs with low molecular weight.

In summary, this series of studies established, for the first time, that in vitro methods can be used to successfully predict oral drug absorption and tissue distribution in horses. The results of these studies have important implications. They will help horses and horse owners by providing a greater selection of effective drugs for treating diseases in horses. They will assist veterinarians by providing them with greater choices of drugs and more information about the potential effectiveness of drugs they prescribe. These studies will also assist the pharmaceutical industry by helping to efficiently screen potential drug candidates for development. Lastly, these studies can be used by regulatory agencies to provide information that may be used as a guide to evaluate oral absorption studies in horses and the effects of formulation on oral drug absorption.