Tomaru, Atsuko; Toshimoto, Kota; Lee, Wooin; Ishigame, Keiko; Sugiyama, Yuichi published the artcile< A Simple Decision Tree Suited for Identification of Early Oral Drug Candidates With Likely Pharmacokinetic Nonlinearity by Intestinal CYP3A Saturation>, Product Details of C10H13ClN2O3S, the main research area is CYP3A pharmacokinetic Intestinal absorption type I nonlinearity; Cytochrome P450 (CYP) 3A; First-pass metabolism; Intestinal absorption; Nonlinear pharmacokinetics; Oral absorption.
To identify oral drugs that likely display nonlinear pharmacokinetics due to saturable metabolism by intestinal CYP3A, our previous report using CYP3A substrate drugs proposed an approach using thresholds for the linear index number (LIN3A = dose/Km; Km, Michaelis-Menten constant for CYP3A) and the intestinal availability (FaFg). Here, we aimed to extend the validity of the previous approach using both CYP3A substrate and non-substrate drugs and to devise a decision tree suited for early drug candidates using in vitro metabolic intrinsic clearance (CLint, vitro) instead of FaFg. Out of 152 oral drugs (including 136 drugs approved in Japan, US or both), type I nonlinearity (in which systemic drug exposure increases in a more than dose-proportional manner) was noted with 82 drugs (54%), among which 58 drugs were identified as CYP3A substrates based on public information. Based on practical feasibility, 41 drugs were selected from CYP3A substrates and subjected to inhouse metabolic assessment. The results were used to determine the thresholds for CLint, vitro (0.45μL/min/pmol CYP3A4) and LIN3A (1.0 L). For four drugs incorrectly predicted, potential mechanisms were looked up. Overall, our proposed decision tree may aid in the identification of early drug candidates with intestinal CYP3A-derived type I nonlinearity.
Journal of Pharmaceutical Sciences (Philadelphia, PA, United States) published new progress about Cytochrome P450 CYP3A inhibitors. 94-20-2 belongs to class amides-buliding-blocks, and the molecular formula is C10H13ClN2O3S, Product Details of C10H13ClN2O3S.
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