Study on In Vitro Metabolism and In Vivo Pharmacokinetics of Beauvericin

Abstract

Beauvericin (BEA) is a well-known mycotoxin produced by many fungi, including Beaveria bassiana. The purpose of this study was to evaluate the in vitro distribution and metabolism characteristics as well as the in vivo pharmacokinetic (PK) profile of BEA. The in vitro metabolism studies of BEA were performed using rat, dog, mouse, monkey and human liver microsomes, cryopreserved hepatocytes and plasma under conditions of linear kinetics to estimate the respective elimination rates. Additionally, LC-UV-MSn (n = 1~2) was used to identify metabolites in human, rat, mouse, dog and monkey liver microsomes. Furthermore, cytochrome P450 (CYP) reaction phenotyping was carried out. Finally, the absolute bioavailability of BEA was evaluated by intravenous and oral administration in rats. BEA was metabolically stable in the liver microsomes and hepatocytes of humans and rats; however, it was a strong inhibitor of midazolam 1′-hydroxylase (CYP3A4) and mephenytoin 4′-hydroxylase (CYP2C19) activities in human liver microsomes. The protein binding fraction values of BEA were >90% and the half-life (T1/2) values of BEA were approximately 5 h in the plasma of the five species. The absolute bioavailability was calculated to be 29.5%. Altogether, these data indicate that BEA has great potential for further development as a drug candidate. Metabolic studies of different species can provide important reference values for further safety evaluation.

Cannabidiol-Based Prodrugs: Synthesis and Bioevaluation

“…The plasma stability of the experimental prodrugs 3a and 3aa , along with CBD 1 , was also checked in plasma (obtained from control Balb/C mice) using a substrate depletion approach. , This experiment was performed using enalapril as a standard that displayed more than 80% degradation within 2 h. Results corroborate with the reported findings. , CBD 1 , as a test candidate, showed negligible degradation in mice plasma. Results demonstrate that CBD 1 has high stability in mice plasma.…”

“…43,44 This experiment was performed using enalapril as a standard that displayed more than 80% degradation within 2 h. Results corroborate with the reported findings. 45,46 CBD 1, as a test candidate, showed negligible degradation in mice plasma. Results demonstrate that CBD 1 has high stability in mice plasma.…”

In Vitro Metabolism and In Vivo Pharmacokinetics Profiles of Hydroxy-α-Sanshool

“…Metabolic stability is also a metric that needs to be examined in drug design, indicating the susceptibility of a compound to biotransformation, and the results are represented by the in vitro T 1/2 and CL int [ 11 ]. Effective delivery of intact drugs to functional targets for action, rather than being hydrolyzed midway, which means that enhanced metabolic stability of the drug is essential for its enhanced efficacy [ 24 ].…”

“…In the past, studies have been involved in studying the PK of the main active ingredients in ZBM including HAS, hydroxy-β-sanshool (HBS), and hydroxy-γ-sanshool (HRS) using both subcutaneous and intravenous injections, and the results showed that after subcutaneous administration, the drug was rapidly absorbed and widely distributed in the plasma, and it was noted that the absolute bioavailability of HAS was high [ 10 ]. In addition, preclinical studies of drugs need to involve studies related to the stability of drug metabolism in vivo or in vitro, such as metabolic stability, protein binding, and bioavailability [ 11 ]. Furthermore, analyzing the metabolism of the drug in different species in vitro is helpful in predicting the role of the drug in human organism metabolism and safety evaluation [ 12 ].…”

Deep Learning with Geometry-Enhanced Molecular Representation for Augmentation of Large-Scale Docking-Based Virtual Screening

“…Drug discovery is an extremely expensive, time-consuming, and interdisciplinary task due to the great efforts required to explore the chemical space of possible compounds and their corresponding activity, efficacy, and safety with various experiments in vivo and in vitro. − To this end, the computer-aided drug discovery (CADD) methods have significantly assisted the progress of modern drug discovery. − Among the diverse CADD techniques, structure-based virtual screening that relies on molecule docking and scoring has been a relatively mature technique. − Because of its efficiency and notable virtual-hits-enrichment effect, virtual screening has been routinely used to find hits that complement a biological target from large libraries of available, often purchasable, chemicals. − However, limited by the computational burden, at present, conventional structure-based virtual screening approaches can typically handle a scale of millions of chemical molecules, although recently a handful of billion-sized virtual screening campaigns have been carried out on elite supercomputing facilities. , …”