Drugs in Horses: Pharmacokinetics and Pharmacodynamics

Lena Olsén 2007. Drugs in horses: pharmacokinetics and pharmacodynamics Doctoral thesis ISSN 1652-6880, ISBN978-91-576-7336-7 In this thesis the fate and effect of some drugs have been examined in horses. Studies have also been performed to explore some factors which may affect the pharmacokinetics and the pharmacodynamics of drugs in horses. Investigations on the drug metabolising enzyme cytochrome P450 3A (CYP3A) in the intestines of horses showed high gene expression and metabolic activity in the proximal parts of the intestines. The results indicate that CYP3A in the intestines of horse plays a major role in the first-pass metabolism of drugs which are substrates for CYP3A. There is a need for an antihistamine for oral therapy of horses. The oral bioavailability of the antihistamine fexofenadine was found to be low, and this drug is therefore unsuitable for oral use in horses. In contrast oral administration of the antihistamine cetirizine resulted in a sufficient uptake. This drug was also found to have a potent antihistaminic effect in horses. Cetirizine may therefore be a suitable antihistamine in equine medicine. The passage of antihistamines, such as fexofenadine and cetirizine, as well as several other xenobiotics, over cell-membranes in various tissues is partly regulated by transport proteins. Studies in this thesis showed that pre-treatment of horses with the antiparasitic agent ivermectin affects the oral bioavailability of fexofenadine and cetirizine. The effect of ivermectin is probably related to interference in the function of the transport proteins. Acute adverse reactions may occur following treatments of horses with procaine benzylpenicillin or potassium or sodium benzylpenicillin. Analysis of adverse reactions reported in 59 horses indicates that allergy may underlie a few of the cases. However, most reactions may be due to toxic effects of procaine. Several mechanisms may contribute to the procaine toxicity. It was shown that the ability of plasma esterases to hydrolyze procaine to non-toxic metabolites was lower in reacting horses compared to non-reacting control horses. Low plasma esterase activity may increase the likelihood for procaine toxicity and constitute one risk factor.