Two dimensional chromatography mass spectrometry: Quantitation of chiral shifts in metabolism of propranolol in bioanalysis

Harps, Lukas Corbinian; Schipperges, Sonja; Bredendiek, Felix; Wuest, Bernhard; Borowiak, Andreas; Parr, Maria Kristina

doi:10.1016/j.chroma.2019.460828

Cited by 6 publications

(9 citation statements)

References 21 publications

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“…Thus, analysis of the glucuronidation of this substrate by a UGT allows the relevant reaction site of 4-hydroxypropranolol for the same enzyme to be inferred. 4-Methoxypropranolol was synthesized chemically according to a method adapted from Oatis et al and Harps et al [33,34] (Supplementary Material). The synthesis was stopped before the final step of demethylation, and thus, 4-methoxypropranolol was obtained.…”

Section: Determination Of the Regioselectivity Of 4-hydroxypropranolo...mentioning

confidence: 99%

See 1 more Smart Citation

Complete Reaction Phenotyping of Propranolol and 4-Hydroxypropranolol with the 19 Enzymes of the Human UGT1 and UGT2 Families

Yang

Liu

Wolber

et al. 2022

IJMS

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Propranolol is a competitive non-selective beta-receptor antagonist that is available on the market as a racemic mixture. In the present study, glucuronidation of propranolol and its equipotent phase I metabolite 4-hydroxypropranolol by all 19 members of the human UGT1 and UGT2 families was monitored. UGT1A7, UGT1A9, UGT1A10 and UGT2A1 were found to glucuronidate propranolol, with UGT1A7, UGT1A9 and UGT2A1 mainly acting on (S)-propranolol, while UGT1A10 displays the opposite stereoselectivity. UGT1A7, UGT1A9 and UGT2A1 were also found to glucuronidate 4-hydroxypropranolol. In contrast to propranolol, 4-hydroxypropranolol was found to be glucuronidated by UGT1A8 but not by UGT1A10. Additional biotransformations with 4-methoxypropanolol demonstrated different regioselectivities of these UGTs with respect to the aliphatic and aromatic hydroxy groups of the substrate. Modeling and molecular docking studies were performed to explain the stereoselective glucuronidation of the substrates under study.

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Section: Determination Of the Regioselectivity Of 4-hydroxypropranolo...mentioning

confidence: 99%

“…The synthesis method of 4-methoxypropranolol was adapted from the method that Oatis et al and Harps et al applied for the synthesis of 4-hydroxypropranolol [33,34]. 4-Methoxy-1-naphthol (1 g) and potassium carbonate (2.5 g) were suspended in 12.5 mL methylethylketone (MEK) and 15 mL epichlorohydrin.…”

Section: Synthesis Of 4-methoxypropranololmentioning

confidence: 99%

Complete Reaction Phenotyping of Propranolol and 4-Hydroxypropranolol with the 19 Enzymes of the Human UGT1 and UGT2 Families

Yang

Liu

Wolber

et al. 2022

IJMS

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“…This compound was chosen because it is metabolized by both CYP2D6 and a number of UGTs. More specifically, CYP2D6 has been found to be responsible for the hydroxylation of propranolol, thereby producing the phase I metabolites 4-, 5-, and 7-hydroxypropranolol [ 31 , 38 , 39 , 40 ]. We have recently demonstrated that propranolol can be glucuronidated by UGT1A7, UGT1A9, UGT1A10, and UGT2A1, while its CYP2D6 metabolite 4-hydroxypropranolol is a substrate for UGT1A7, UGT1A8, UGT1A9, and UGT2A1 [ 30 ].…”

Section: Discussionmentioning

confidence: 99%

“…Tris buffer, potassium chloride, glycerol and Triton X-100 were sourced from Carl Roth GmbH & Co. KG (Karlsruhe, Germany); UDPGA, (±)-propranolol, ( R )-propranolol, and (±)-4-hydroxypropranolol were obtained from Sigma-Aldrich (Taufkirchen, Germany); (±)-5-hydroxypropranolol was purchased from Cayman Chemical Company (Ann Arbor, MI, USA); the NADPH regeneration system was sourced from Promega Corporation (Madison, WI, USA); and 4-methoxypropranolol was synthesized in-house as described previously [ 30 , 31 , 32 ]. Ammonium hydrogen carbonate was purchased from VWR International GmbH (Darmstadt, Germany); and phosphate buffered saline (PBS, pH 7.4) was purchased from VWR Chemicals LLC (Solon, OH, USA).…”

Section: Methodsmentioning

confidence: 99%

Mutual Modulation of the Activities of Human CYP2D6 and Four UGTs during the Metabolism of Propranolol

Yang,

Sharma,

Bureik

et al. 2023

CIMB

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Cytochromes P450 (CYP) and UDP-glucuronosyltransferases (UGT) are two enzyme families that play an important role in drug metabolism, catalyzing either the functionalization or glucuronidation of xenobiotics. However, their mutual interactions are poorly understood. In this study, the functional interactions of human CYP2D6 with four human UGTs (UGT1A7, UGT1A8, UGT1A9, and UGT2A1) were investigated using our previously established co-expression model system in the fission yeast Schizosaccharomyces pombe. The substrate employed was propranolol because it is well metabolized by CYP2D6. Moreover, the CYP2D6 metabolite 4-hydroxypropranolol is a known substrate for the four UGTs included in this study. Co-expression of either UGT1A7, UGT1A8, or UGT1A9 was found to increase the activity of CYP2D6 by a factor of 3.3, 2.1 or 2.8, respectively, for the conversion of propranolol to 4-hydroxypropranolol. In contrast, UGT2A1 co-expression did not change CYP2D6 activity. On the other hand, the activities of all four UGTs were completely suppressed by co-expression of CYP2D6. This data corroborates our previous report that CYP2D6 is involved in functional CYP-UGT interactions and suggest that such interactions can contribute to both adverse drug reactions and changes in drug efficacy.

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“…Highly sensitive hyphenated mass detectors for 2D-LC allow the detection of drugs and their metabolites. The enantiomers of propranolol and its metabolites were separated and quantified in human urine samples, allowing for a calculation of the excretion rates [ 78 ]. Another 2D LC-MS/MS was used for the simultaneous quantification of fluoxetine and norfluoxetine enantiomers in biological samples (human milk) using direct sample injection.…”

Section: Chiral Analysis In Pharmacokineticsmentioning

confidence: 99%

Enantioselectivity in Drug Pharmacokinetics and Toxicity: Pharmacological Relevance and Analytical Methods

et al. 2021

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Enzymes, receptors, and other binding molecules in biological processes can recognize enantiomers as different molecular entities, due to their different dissociation constants, leading to diverse responses in biological processes. Enantioselectivity can be observed in drugs pharmacodynamics and in pharmacokinetic (absorption, distribution, metabolism, and excretion), especially in metabolic profile and in toxicity mechanisms. The stereoisomers of a drug can undergo to different metabolic pathways due to different enzyme systems, resulting in different types and/or number of metabolites. The configuration of enantiomers can cause unexpected effects, related to changes as unidirectional or bidirectional inversion that can occur during pharmacokinetic processes. The choice of models for pharmacokinetic studies as well as the subsequent data interpretation must also be aware of genetic factors (such as polymorphic metabolic enzymes), sex, patient age, hepatic diseases, and drug interactions. Therefore, the pharmacokinetics and toxicity of a racemate or an enantiomerically pure drug are not equal and need to be studied. Enantioselective analytical methods are crucial to monitor pharmacokinetic events and for acquisition of accurate data to better understand the role of the stereochemistry in pharmacokinetics and toxicity. The complexity of merging the best enantioseparation conditions with the selected sample matrix and the intended goal of the analysis is a challenge task. The data gathered in this review intend to reinforce the importance of the enantioselectivity in pharmacokinetic processes and reunite innovative enantioselective analytical methods applied in pharmacokinetic studies. An assorted variety of methods are herein briefly discussed.

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Two dimensional chromatography mass spectrometry: Quantitation of chiral shifts in metabolism of propranolol in bioanalysis

Cited by 6 publications

References 21 publications

Complete Reaction Phenotyping of Propranolol and 4-Hydroxypropranolol with the 19 Enzymes of the Human UGT1 and UGT2 Families

Complete Reaction Phenotyping of Propranolol and 4-Hydroxypropranolol with the 19 Enzymes of the Human UGT1 and UGT2 Families

Mutual Modulation of the Activities of Human CYP2D6 and Four UGTs during the Metabolism of Propranolol

Enantioselectivity in Drug Pharmacokinetics and Toxicity: Pharmacological Relevance and Analytical Methods

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