Pharmacokinetics and pharmacodynamics of ramipril and ramiprilat after intravenous and oral doses of ramipril in healthy horses.

This research study investigates the pharmacokinetics (how the body processes a drug) and pharmacodynamics (the effects of a drug on the body) of a medication called ramipril, and its active form, ramiprilat, in horses. The results show that even though the oral bioavailability of ramiprilat is low, sufficient amounts can be absorbed and converted to ramiprilat in the body to significantly lower the activity of serum angiotensin-converting enzyme (ACE), a target for managing blood pressure, when a dose of 0.80 mg/kg ramipril is used.

Research Design and Methods

• The study was designed as a cross-over experiment involving six healthy horses. This means that each horse experienced each treatment in different periods, minimizing potential biases from individual differences between the animals.
• The horses were given different doses of ramipril (IV at 0.050 mg/kg, PO at 0, 0.050, 0.10, 0.20, 0.40 and 0.80 mg/kg) and their blood pressure was monitored. Blood samples were also collected at specific time points.

Investigation Techniques

• Using liquid chromatography tandem mass spectrometry (LC-MS/MS), a powerful analytical technique, the researchers were able to measure the concentrations of ramipril and ramiprilat in the serum.
• ACE activity was gauged using a spectrophotometric technique that measures how much light the sample absorbs.

Key Findings

• The systemic bioavailability (the degree and rate at which the active form of the drug is absorbed and becomes available at the site of drug action) of ramiprilat after oral administration of ramipril was between 6-9%. This indicates a relatively low absorption rate from the gut into the systemic circulation.
• Despite the limited bioavailability, the levels of ACE inhibition observed were significant. Intravenous ramipril resulted in nearly complete inhibition (98.88%) of ACE, while the five oral doses resulted in varying degrees of inhibition, with the 0.80 mg/kg dose achieving approximately 85% inhibition.
• Importantly, no changes in blood pressure were observed during the study, suggesting that while ACE was significantly inhibited, it did not cause hypotension (low blood pressure) in these healthy horses.

Study Implications

• The results indicate that even with low oral bioavailability, ramipril can be adequately absorbed and converted to its active form ramiprilat, to yield significant ACE inhibition in horses.
• However, as this study was performed in healthy horses, further research is needed to thoroughly investigate ramipril’s efficacy and safety in equine patients, particularly those with conditions that ACE inhibitors like ramipril are typically used to treat, such as heart failure or hypertension.