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Usage

Uses

Used in Pharmaceutical Industry:
4-Hydroxydebrisoquine is used as an active pharmaceutical ingredient for the development of antihypertensive medications. Its role in this application is attributed to the fact that it is a metabolite of Debrisoquine Sulfate, which is known for its potent antihypertensive effects.
Used in Research and Development:
In the field of research and development, 4-Hydroxydebrisoquine serves as a valuable compound for studying the metabolic pathways and pharmacokinetics of Debrisoquine Sulfate. This understanding can lead to the development of more effective and safer antihypertensive drugs.
Used in Drug Metabolism Studies:
4-Hydroxydebrisoquine is used as a biomarker in drug metabolism studies, particularly in the context of genetic variations that affect the metabolism of certain drugs. This application is crucial for personalized medicine, as it helps in understanding how different individuals metabolize specific drugs, leading to tailored treatment plans.
Used in Toxicology and Safety Assessment:
In the realm of toxicology and safety assessment, 4-Hydroxydebrisoquine is utilized to evaluate the safety and potential side effects of Debrisoquine Sulfate and related compounds. This information is vital for determining the safe dosages and potential risks associated with the use of these antihypertensive agents.

InChI:InChI=1/C10H13N3O/c11-10(12)13-5-7-3-1-2-4-8(7)9(14)6-13/h1-4,9,14H,5-6H2,(H3,11,12)

Upstream product

• 1131-64-2 debrisoquine 

Relevant academic research and scientific papers

Complementary DNA cloning, functional expression and characterization of a novel cytochrome P450, CYP2D50, from equine liver

Members of the CYP2D family constitute only about 2-4% of total hepatic CYP450s, however, they are responsible for the metabolism of 20-25% of commonly prescribed therapeutic compounds. CYP2D enzymes have been identified in a number of different species. However, vast differences in the metabolic activity of these enzymes have been well documented. In the horse, the presence of a member of the CYP2D family has been suggested from studies with equine liver microsomes, however its presence has not been definitively proven. In this study a cDNA encoding a novel CYP2D enzyme (CYP2D50) was cloned from equine liver and expressed in a baculovirus expression system. The nucleotide sequence of CYP2D50 was highly homologous to that of human CYP2D6 and therefore the activity of the enzyme was characterized using dextromethorphan and debrisoquine, two isoform selective substrates for the human orthologue. CYP2D50 displayed optimal catalytic activity with dextromethorphan using molar ratios of CYP2D50 to NADPH CYP450 reductase of 1:15. Although CYP2D50 and CYP2D6 shared significant sequence homology, there were striking differences in the catalytic activity between the two enzymes. CYP2D50 dextromethorphan-O-demethylase activity was nearly 180-fold slower than the human counterpart, CYP2D6. Similarly, rates of formation of 4-hydroxydebrisoquine activity were 50-fold slower for CYP2D50 compared to CYP2D6. The results of this study demonstrate substantial interspecies variability in metabolism of substrates by CYP2D orthologues in the horse and human and support the need to fully characterize this enzyme system in equids.

Identification of human cytochrome P450s that metabolise anti-parasitic drugs and predictions of in vivo drug hepatic clearance from in vitro data

Objective: Knowledge about the metabolism of anti-parasitic drugs (APDs) will be helpful in ongoing efforts to optimise dosage recommendations in clinical practise. This study was performed to further identify the cytochrome P450 (CYP) enzymes that metabolise major APDs and evaluate the possibility of predicting in vivo drug clearances from in vitro data. Methods: In vitro systems, rat and human liver microsomes (RLM, HLM) and recombinant cytochrome P450 (rCYP), were used to determine the intrinsic clearance (CLint) and identify responsible CYPs and their relative contribution in the metabolism of 15 commonly used APDs. Results and discussion: CLint determined in RLM and HLM showed low (r2=0.50) but significant (Pint values were scaled to predict in vivo hepatic clearance (CLH) using the 'venous equilibrium model'. The number of compounds with in vivo human CL data after intravenous administration was low (n=8), and the range of CL values covered by these compounds was not appropriate for a reasonable quantitative in vitro-in vivo correlation analysis. Using the CLH predicted from the in vitro data, the compounds could be classified into three different categories: high-clearance drugs (> 70% liver blood flow; amodiaquine, praziquantel, albendazole, thiabendazole), low-clearance drugs (int drug categories. The identified CYPs for some of the drugs provide a basis for how these drugs are expected to behave pharmacokinetically and help in predicting drug-drug interactions in vivo.

The molecular and enzyme kinetic basis for the diminished activity of the cytochrome P450 2D6.17 (CYP2D6.17) variant: Potential implications for CYP2D6 phenotyping studies and the clinical use of CYP2D6 substrate drugs in some African populations

In this study, the basis for the diminished capacity of CYP2D6.17 to metabolise CYP2D6 substrate drugs and the possible implications this might have for CYP2D6 phenotyping studies and clinical use of substrate drugs were investigated in vitro. Enzyme kinetic analyses were performed with recombinant CYP2D6.1, CYP2D6.2, CYP2D6.17 and CYP2D6.T107I using bufuralol, debrisoquine, metoprolol and dextromethorphan as substrates. In addition, the intrinsic clearance of 10 CYP2D6 substrate drugs by CYP2D6.1 and CYP2D6.17 was determined by monitoring substrate disappearance. CYP2D6.17 exhibited generally higher Km values compared to CYP2D6.1. The Vmax values were generally not different except for metoprolol α-hydroxylation with the Vmax value for CYP2D6.17 being half that of CYP2D6.1. CYP2D6.1 and CYP2D6.2 displayed similar kinetics with all probe drugs except for dextromethorphan O-demethylation with the intrinsic clearance value of CYP2D6.2 being half that of CYP2D6.1. CYP2D6.17 exhibited substrate-dependent reduced clearances for the 10 substrates studied. In a clinical setting, the clearance of some drugs could be affected more than others in individuals with the CYP2D6* 17 variant. The CYP2D6* 17 allele might, therefore, contribute towards the poor correlation of phenotyping results when using different probe drugs in African populations. To investigate effects of CYP2D6* 17 mutations on the structure of the enzyme, a homology model of CYP2D6 was built using the CYP2C5 crystal structure as a template. The results suggest an alteration in position of active-site residues in CYP2D6.17 as a possible explanation for the reduced activity of the enzyme.

Isoquinoline derivatives

2-Amidino-4-hydroxy-1,2,3,4-tetrahydroisoquinoline, prepared from 4-hydroxy-1,2,3,4-tetrahydroisoquinoline and a compound which yields the amidino group, as well as its salts, are described.