Purpose(s)
Ursolic acid (UA) is a common pentacyclic triterpene phytochemical with a variety of physiological activities.
However, UA is classified as a class IV drug in BCS system so that its development as an oral drug is limited.
Pulmonary delivery is an effective way to improve the bioavailability of drugs with low absorption.
In this study, UA was selected as a model drug to compare the alterations in pharmacokinetic behaviors between pulmonary and oral administration.
Method(s)
1. Pulmonary Delivery by Nose-Only Inhalation Exposure and Intratracheal Instillation
2. Plasma Pharmacokinetics and in vivo Distribution Study
3. In vitro Enzyme Kinetic Study
4. Analysis by LC-MS/MS
Result(s)
Compared with oral administration, the plasma concentration of UA increased rapidly after pulmonary administration, and the bioavailability increased about 80 times. UA instantly accumulated in the lungs after pulmonary administration, and the pulmonary AUC0-t/dose increased by 114 times compared to oral dosing. Incubation experiments showed that the metabolism of UA in rat lung microsomes was significantly reduced compared with that in liver microsomes, in which the clearance rate of phase I and phase II metabolism was reduced by 14.7 times and 1.4 times respectively. These results indicated that pulmonary administration could improve the bioavailability of UA and reduce its metabolism.
Conclusion(s)
In summary, this study systematically explored the pharmacokinetic characteristics of UA, an active phytochemical in BCS IV class, following different administration routes in rats. Plasma pharmacokinetic profile, tissue distribution, and microsomal metabolism from different administration routes were investigated. We found that UA was absorbed rapidly after pulmonary administration, which could reach a sufficient drug concentration quickly. The bioavailability of UA was significantly increased after pulmonary administration compared with intragastric administration, and the pulmonary targeting effect was improved in the meantime. It was also found that the metabolism level of UA in lung microsomes was much lower than that in liver microsomes, which confirmed the results in vivo. Taken together, rapid absorption, good targeting, and reduced metabolism make the pulmonary administration a promising approach for the application of UA. With this study, we hope to afford new insights into the pulmonary drug delivery for the improvement of herbal medicinal compounds and increase the possibility and pace of entering clinical.