Unusual Biotransformation Reactions of Drugs and Drug Candidates

Abstract

Detailed assessment of the fate of drugs in non-clinical test species and humans is essential to ensure the safety and efficacy of medicines in patients. In this context, biotransformation of drugs and drug candidates has been an area of keen interest over many decades in the pharmaceutical industry as well as academia. Although many of the enzymes and biotransformation pathways involved in the metabolism of xenobiotics and more specifically drugs have been well-characterized, each drug molecule is unique and constitutes specific challenges for the biotransformation scientist. In this mini-review written for the Special Issue on the occasion of the 50 th Anniversary celebration of DMD and to celebrate contributions of Prof. F. Peter Guengerich, one of the pioneers of the drug metabolism field, recently reported "unusual" biotransformation reactions are presented. Scientific and technological advances in the "toolbox" of the biotransformation scientists are summarized. As the pharmaceutical industry continues to explore therapeutic modalities different from the traditional small molecule drugs, the new challenges confronting the biotransformation scientist as well as future opportunities are discussed.

Ninety-eight semesters of cytochrome P450 enzymes and related topics—What have I taught and learned?

“…Over the years, we have been interested in the more unusual reactions that P450s catalyze, and I have written some reviews on this topic ( 108 , 109 , 110 , 111 ). Almost all of the oxidations can be rationalized in the context of compound I (FeO 3+ ) or, in a few cases, compound 0 (FeO 2 ¯) chemistry ( 82 , 112 ).…”

The Importance of Tracking “Missing” Metabolites: How and Why?

“…24 Regardless of the difficulty in synthesis, 14 C is the typical label of choice for most drug candidates in development since it can be introduced at a metabolically stable position. However, in some cases, the 14 Clabel could be lost through unexpected biotransformation pathways, 25 which impacts the overall mass balance and detection of both primary and secondary metabolites due to loss of the radiotracer.…”

Alpibectir: Early Qualitative and Quantitative Metabolic Profiling from a First-Time-in-Human Study by Combining19F-NMR (Nuclear Magnetic Resonance),1H-NMR, and High-Resolution Mass Spectrometric Analyses

“…These "cold" studies bring an efficiency and flexibility, when used as informative tools; however, the same disadvantages intrinsic to all mass spectrometric approaches still exist. When using nonradiolabelled studies, detection of non-predicted or unusual biotransformations [Isin et al, 2023] and difficult-to-detect metabolites [Wang et al, 2023] remain challenging; ramifications of missing metabolites can impact key decision points in later drug development. Mitigating these issues relies heavily upon the skill of the biotransformation scientist, where awareness of the inherent bias of HRMS approaches requires skilled oversight and some degree of manual data interrogation [Weston et al, 2022].…”