Biotransformation novel advances - 2021 year in review

Abstract

Biotransformation field is constantly evolving with new molecular structures and discoveries of metabolic pathways that impact efficacy and safety. Recent review by Kramlinger et al. (2022) nicely captures the future (and the past) of highly impactful science of biotransformation (see the first article). Based on the selected articles, this review was categorized into three sections: (1) new modalities biotransformation, (2) drug discovery biotransformation, and (3) drug development biotransformation (Table 1).

Figure 1.

Bioactivation pathway of empagliflozin to 4-OH-CTA. Adapted from Taub et al. (2015).

Figure 2.

(A) Structure of givosiran and its metabolites. (B) Structures of (A) unmodified, 2′-O-methyl (2′-OMe), 2′-deoxy-2′-fluoro (2′-F), and phosphorothioate (PS) modified nucleotides; (C) triantennary GalNAc linker from givosiran.

Figure 3.

Known biotransformation products of ligand-conjugated siRNA and proposed biotransformation mechanisms: B, RNA base adenine, guanine, cytosine, or uracil; R, 2′-ribose modification, i.e. 2′-F or 2′-OMe. SS is sense strand and AS is antisense strand. Figure from Humphreys et al. (2020) (Copyright 2020, American Chemical Society).

Figure 4.

Carbazeran enzymatic conversation to 4-oxo-carbazeran aldehyde oxidase (AO) was chosen as a selective probe substrate for the contribution of various tissue in its metabolism.

Figure 5.

JAK inhibitor that displays poor lung exposure due to AO metabolism (left) and a JAK inhibitor lacking AO susceptibility that displays high lung exposure (right). Arrow indicates site of AO oxidation.

Figure 6.

Evaluating the ability of in vitro CYP3A time-dependent inhibition (TDI) data to predict clinically significant drug-drug interactions (DDI). AUC: Area under the plasma concentrationtime curve; k_inact: maximal inactivation rate; K_I: time-dependent inhibition constant; K_i: reversible inhibition constant.

Figure 7.

The role of PGRMC1 in CYP2E1 stability as well as acetaminophen metabolism and toxicity.

Figure 8.

Major metabolic structures of risdiplam.

Figure 9.

Known metabolic pathways for the oxidative cleavage of nonsteroidal anti-inflammatory prodrug nabumetone to its biologically active metabolite 6-MNA. ALDH: Aldehyde dehydrogenase.

Figure 10.

(A) Identification of the potent and selective Na_V1.7 inhibitor DS-1971a via optimization of the previously disclosed benzenesulfonamide chemotypes from 1 and PF-05089771. (B) Major metabolites of DS-1971a in animals and human.

Figure 11.

Interconversion of the two diastereomers of darolutamide via keto-darolutamide.

Figure 12.

Proposed sites of oxidations of tropifexor.

Figure 13.

Biotransformation pathways of ibrutinib.

Figure 14.

Proposed mechanism of oxidation of RP101075 by MAO-B.

Figure 15.

Metabolism of ozanimod by gut microbiota.

Figure 16.

Direct glucuronidation of licogliflozin to M17, M23, and M27.