drug-drug interactions

Mitotane (NCI-C04933) is a derivative of the insecticide DICHLORODIPHENYLDICHLOROETHANE that specifically inhibits cells of the adrenal cortex and their production of hormones. It is used to treat adrenocortical tumors and causes CNS damage, but no bone marrow depression.

Pitavastatin calcium (NK-104) is a potent inhibitor of HMG-CoA reductase (Ki: 1.7 nM). It lowers both total cholesterol and low-density lipoprotein cholesterol in animals and humans. Metabolism of pitavastatin by the cytochrome P450 system is minimal, reducing the risk of drug-drug interactions.

SJPUT-328 is a potent activator of the Pregnane X Receptor (PXR), which plays a crucial role in drug metabolism and drug interactions.

(E)-2,6-Di-tert-butyl-4-(4-(diethylamino)styryl)pyrylium TFA (Compound 4a) functions as a Gram-negative outer membrane permeabilizer by targeting Met47 in LptA to disrupt LptA LptC interactions, exhibiting synergistic antibacterial activity. This compound, when in the form of (trifluoromethanesulfonate), enhances the efficacy of pol B against both wild-type and multi-drug resistant A. baumannii and E. coli strains. Additionally, (E)-2,6-Di-tert-butyl-4-(4-(diethylamino)styryl)pyrylium (trifluoromethanesulfonate) serves as an adjuvant for antibiotics combating multi-drug resistant Gram-negative bacteria.

2,5-Dioxopyrrolidin-1-yl 6-acrylamidohexanoate can be used as a cross-linking agent to immobilise matrix proteins on gel surfaces, enhancing cell-matrix interactions, and is widely applied in biochemical experiments and drug synthesis research.

BNS808 is an orally active, selective CB1R antagonist with an IC50 of 0.8 nM, demonstrating significant selectivity for CB2R and minimal brain penetration. It is being studied for the treatment of obesity and related metabolic complications, such as metabolic dysfunction-associated steatotic liver disease (MASLD). BNS808 reduces drug exposure to the central nervous system, enhancing safety, and minimizes drug interactions through high plasma protein binding.

5-Benzyloxygramine is an N protein PPI orthosteric stabilizer that exhibits both antiviral and N-NTD protein-stabilizing activities. It stabilizes the N-NTD dimers through simultaneous hydrophobic interactions with both partners, resulting in abnormal N protein oligomerization, which was further confirmed in cell studies[1]. [1]. Shan-Meng Lin, et al. Structure-Based Stabilization of Non-native Protein-Protein Interactions of Coronavirus Nucleocapsid Proteins in Antiviral Drug Design. J Med Chem. 2020 Mar 26;63(6):3131-3141.

N-hydroxy Riluzole is a metabolite of the antiglutamatergic agent riluzole .1It is formed from riluzole predominantly by the cytochrome P450 (CYP) isoform CYP1A2 in human hepatic microsomes. 1.Sanderink, G.J., Bournique, B., Stevens, J., et al.Involvement of human CYP1A isoenzymes in the metabolism and drug interactions of riluzole in vitroJ. Pharmacol. Exp. Ther.282(3)1465-1472(1997)

Imidafenacin metabolite M4 is a metabolite of the muscarinic acetylcholine receptor antagonist imidafenacin.1It is formed from imidafenacin by the cytochrome P450 (CYP) isoform CYP3A4. 1.Kanayama, N., Kanari, C., Masuda, Y., et al.Drug-drug interactions in the metabolism of imidafenacin: Role of the human cytochrome P450 enzymes and UDP-glucuronic acid transferases, and potential of imidafenacin to inhibit human cytochrome P450 enzymesXenobiotica37(2)139-154(2007)

Dolutegravir O-β-D-glucuronide is a metabolite of the HIV integrase inhibitor dolutegravir .1It is formed from dolutegravir primarily by the UDP-glucuronosyltransferase (UGT) isoform UGT1A1in vivobut is also metabolized by UGT1A9 in human liver and kidney microsomes and UGT1A3 in human intestinal microsomes.2,1 1.Liu, S.N., Lu, J.B., Watson, C.J.W., et al.Mechanistic assessment of extrahepatic contributions to glucuronidation of integrase strand transfer inhibitorsDrug Metab. Dispos.47(5)535-544(2019) 2.Reese, M.J., Savina, P.M., Generaux, G.T., et al.In vitro investigations into the roles of drug transporters and metabolizing enzymes in the disposition and drug interactions of dolutegravir, a HIV integrase inhibitorDrug Metab. Dispos.41(2)353-361(2013)

6'7'-Epoxybergamottin is a furanocoumarin found in grapefruit. It is a potent inhibitor of the cytochrome P450 (CYP) isoform CYP3A4 with an IC50 value of 0.30 ppm in a cell-free assay, 0.33 μM in HL7 human liver cells, and 0.22 μM in S9 human intestine cells. It has been studied in the context of drug interactions with grapefruit constituents. It is found in grapefruit juice at concentrations of 0.1-7.4 μM and inhibits the transport of talinolol , a permeability glycoprotein (P-gp/ABCB1) transporter substrate, across Caco-2 cell monolayers (IC50 = 0.7 μM). 6'7'-Epoxybergamottin also has insecticidal properties with a concentration of 5 μg/cm2 leading to 100% mortality of adult olive fruit flies.

Isosilybin (Isosilibinin) and Silybin might be suitable candidates to design potent PXR antagonists to prevent drug-drug interactions via CYP3A4 in cancer patients.

Ga(III)protoporphyrin-IX, a model for interporphyrin interactions in malaria pigment, possesses potent antibacterial effects against gram-negative, gram-positive, and acid-fast bacteria. It exhibits high solubility in methanol (MeOH) and serves as a malarial pigment analogue for drug development, as well as a potential antibacterial agent.

Tetradecanedioic acid (Tetradecanedicarboxylate) is a long-chain fatty acid that is a type of endogenous metabolite. It can serve as a candidate biomarker for drug-drug interactions mediated by organic anion transporting peptides.

1. Epiberberine may be caused drug interactions based on CYP2D6 enzyme. 2. Epiberberine has anti-adipogenic effect is mediated by downregulation of the Raf MEK1 ERK1 2 and AMPKα Akt pathways during 3T3-L1 adipocyte differentiation. 3. Epiberberine, as the brightest FSA emitter among the alkaloids, can also serve as an efficient conformation probe for HTG DNA and discriminate the DNA G-quadruplex from the RNA counterpart.

5-HT7 receptor ligand 1 (Compound 5c) is a potent 5-HT7 receptor ligand with a K i value of 8 nM, exhibiting non-hepatotoxic properties and moderate potential for drug-drug interactions with CYP3A4 or CYP2D6 substrates [1].

LY3154885 is an orally active dopamine D1 receptor orthosteric modulator (PAM) that reduces the risk of drug-drug interactions (DDI).

Coproporphyrin I dihydrochloride is an appropriate clinical biomarker to recapitulate drug-drug interactions mediated by OATP inhibition.

ARRY-403, also known as AMG-151, is an orally available allosteric glucokinase (GK) activator developed for the treatment of type 2 diabetes mellitus (T2DM). ARRY-403 has many favorable physicochemical characteristics and ADME properties (low potential to cause drug–drug interactions (DDIs). ARRY-403 potently activates human glucokinase (GK) in vitro (EC50 = 79 nM at 5 mM glucose), with an S0.5 = 0.93 mM glucose (ARRY-403 at 5 mM) and Vmax = 134% compared to the no activator control. It possesses good in vitro drug-like properties (aqueous solubility, cell permeability, low low potential for drug-drug interactions, low predicted hepatic clearance), and selectivity against broad panels of receptors and enzymes.

Lipid 11 (Compound Lipid 1) is a cationic lipid designed for nucleic acid delivery. It forms lipid nanoparticles (LNPs) through electrostatic interactions with nucleic acids, such as ceDNA. By using its cationic amine groups, Lipid 11 complexes with negatively charged nucleic acids, enabling cellular uptake and release of the nucleic acid cargo. Lipid 11 shows potential for use in the development of gene therapy drug delivery systems.

Trehalose C12 (α-D-Glucopyranosyl-α-D-glucopyranoside monododecanoate) is a non-reducing disaccharide utilized for its amphiphilic properties as an emulsifier, surfactant, encapsulating material, and in biochemical research on cellular processes and membrane interactions.

Hexaethylene glycol monohexadecyl ether is a nonionic surfactant within the polyethylene glycol (PEG) ether family. It features a hydrophilic head and a lipophilic tail, making it versatile for numerous applications. Specifically, Hexaethylene glycol monohexadecyl ether is commonly employed in membrane protein research to dissolve and stabilize proteins for structural analysis techniques like X-ray crystallography and electron microscopy. Additionally, it is utilized in various industrial and research contexts, such as drug delivery systems, nanotechnology, and diagnostic analysis. Its unique properties make it ideal for facilitating interactions between molecules with differing physicochemical properties.

DDMAB, or didodecyldimethylammonium bromide, is a cationic surfactant widely utilized in various industrial and research contexts. As a member of the quaternary ammonium compounds family, it features a positively charged head and a hydrophobic tail, enabling its function as a detergent, emulsifier, and antimicrobial agent. Known for its ability to disrupt cell membranes, DDMAB is frequently employed in microbiology for the selective isolation and identification of bacteria. In nanotechnology, it is used for synthesizing metal nanoparticles and other materials. Additionally, DDMAB's interactions with cell membranes and its ability to penetrate them highlight its potential applications in drug delivery, gene therapy, and other medical fields.