LAUSR.org creates dashboard-style pages of related content for over 1.5 million academic articles. Sign Up to like articles & get recommendations!

A Novel Method for Predicting the Human Inherent Clearance and Its Application in the Study of the Pharmacokinetics and Drug–Drug Interaction between Azidothymidine and Fluconazole Mediated by UGT Enzyme

Photo from wikipedia

In order to improve the benefit–risk ratio of pharmacokinetic (PK) research in the early development of new drugs, in silico and in vitro methods were constructed and improved. Models of… Click to show full abstract

In order to improve the benefit–risk ratio of pharmacokinetic (PK) research in the early development of new drugs, in silico and in vitro methods were constructed and improved. Models of intrinsic clearance rate (CLint) were constructed based on the quantitative structure–activity relationship (QSAR) of 7882 collected compounds. Moreover, a novel in vitro metabolic method, the Bio-PK dynamic metabolic system, was constructed and combined with a physiology-based pharmacokinetic model (PBPK) model to predict the metabolism and the drug–drug interaction (DDI) of azidothymidine (AZT) and fluconazole (FCZ) mediated by the phase II metabolic enzyme UDP-glycosyltransferase (UGT) in humans. Compared with the QSAR models reported previously, the goodness of fit of our CLint model was slightly improved (determination coefficient (R2) = 0.58 vs. 0.25–0.45). Meanwhile, compared with the predicted clearance of 61.96 L/h (fold error: 2.95–3.13) using CLint (8 µL/min/mg) from traditional microsomal experiment, the predicted clearance using CLint (25 μL/min/mg) from Bio-PK system was increased to 143.26 L/h (fold error: 1.27–1.36). The predicted Cmax and AUC (the area under the concentration–time curve) ratio were 1.32 and 1.84 (fold error: 1.36 and 1.05) in a DDI study with an inhibition coefficient (Ki) of 13.97 μM from the Bio-PK system. The results indicate that the Bio-PK system more truly reflects the dynamic metabolism and DDI of AZT and FCZ in the body. In summary, the novel in silico and in vitro method may provide new ideas for the optimization of drug metabolism and DDI research methods in early drug development.

Keywords: drug interaction; drug drug; method; drug; clearance; clint

Journal Title: Pharmaceutics
Year Published: 2021

Link to full text (if available)


Share on Social Media:                               Sign Up to like & get
recommendations!

Related content

More Information              News              Social Media              Video              Recommended



                Click one of the above tabs to view related content.