The Macrolide Everolimus Forms an Unusual Metabolite in Animals and Humans: Identification of a Phosphocholine Ester

Zollinger, Markus; Sayer, Claudia; Dannecker, Robert; Schüler, W.; Sedrani, Richard

doi:10.1124/dmd.108.020651

Cited by 8 publications

(8 citation statements)

References 13 publications

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“…The ions of m/z 184 and 86 were identical to those observed in the product ion spectra of 1-3 and 2-2 mentioned previously. The product ion spectrum was consistent with that of the everolimus POPC conjugate detected in human and multiple preclinical species (Zollinger et al, 2008). NMR Spectroscopy.…”

Section: Compound and Matrix Parentmentioning

confidence: 57%

“…On the other hand, the hydroxylation products of compound 1 or 2 do not appear to be closely related to the structures of the endogenous substrates of CPT, which include DAGs possessing varied lengths of saturated or unsaturated fatty acid chains (usually 16-22 carbons) and a primary alcohol group, demonstrating that CPT can recognize molecules whose chemical scaffold differs from those of its endogenous substrates. Previously, Zollinger et al (2008) reported that everolimus, a potent immunosuppressant, formed a POPC ester via direct conjugation of a hydroxyl group as a prominent metabolite in rats, mice, cynomolgus monkeys, and humans. Formation of POPC conjugates of everolimus was also unexpected in light of the structural differences between DAGS and everolimus.…”

Section: Discussionmentioning

confidence: 99%

“…The activity of CPT was also assessed by incubating everolimus (10 mM) with rat hepatocytes (1 Â 10 6 cells/ml) under the same conditions described above and by analyzing for the presence of the phosphocholine (POPC) conjugate reported previously (Zollinger et al, 2008).…”

Section: Methodsmentioning

confidence: 99%

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Phosphocholine Conjugation: An Unexpected In Vivo Conjugation Pathway Associated with Hepatitis C NS5B Inhibitors Featuring A Bicyclo[1.1.1]Pentane

Zhuo

Cantone

Wang

et al. 2016

Drug Metabolism and Disposition

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, exhibited low turnover in incubations with liver S9 or hepatocytes (rat, human), with hydroxylation of the bicyclic moiety being the only metabolic pathway observed. In subsequent disposition studies using bile duct-cannulated rats, the metabolite profiles of bile samples revealed, in addition to multiple products of bicyclopentane oxidation, unexpected metabolites characterized by molecular masses that were 181 Da greater than those of compound 1 or 2. Further liquid chromatography/multiple-stage mass spectrometry and nuclear magnetic resonance analysis of the isolated metabolite of compound 1 demonstrated the presence of a phosphocholine (POPC) moiety bound to the methine carbon of the bicyclic moiety through an ester bond. The POPC conjugate of the nonstructural protein 5B inhibitors was assumed to result from two sequential reactions: hydroxylation of the bicyclic methine to a tertiary alcohol and addition of POPC by cytidine-diphosphocholine: 1,2-diacylglycerol cholinephosphotransferase, an enzyme responsible for the final step in the biosynthesis of phosphatidylcholine. However, this pathway could not be recapitulated using cytidinediphosphocholine-supplemented liver S9 or hepatocytes because of inadequate formation of the hydroxylation product in vitro. The observation of this unexpected pathway prompted concerns about the possibility that compounds 1 and 2 might interfere with routine phospholipid synthesis. These results demonstrate the participation in xenobiotic metabolism of a process whose function is ordinarily limited to the synthesis of endogenous compounds.

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Section: Compound and Matrix Parentmentioning

confidence: 57%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Phosphocholine Conjugation: An Unexpected In Vivo Conjugation Pathway Associated with Hepatitis C NS5B Inhibitors Featuring A Bicyclo[1.1.1]Pentane

Zhuo

Cantone

Wang

et al. 2016

Drug Metabolism and Disposition

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show abstract

“…In a recent publication, a phosphocholine metabolite has been described for a hepatitis C NS5B inhibitor (Zhuo et al, 2016). Furthermore, the formation of a phosphocholine ester has been described for the macrolide everolimus as well (Zollinger et al, 2008). This phosphocholine metabolite could be considered a downstream metabolite from the phosphoethanolamine conjugates, formed via phospholipid N-methyltransferases (Schneider and Vance, 1979).…”

Section: Downloaded Frommentioning

confidence: 99%

Metabolism of the MEK1/2 Inhibitor Pimasertib Involves a Novel Conjugation with Phosphoethanolamine in Patients with Solid Tumors

Scheible¹,

Kraetzer²,

Marx³

et al. 2016

Drug Metab Dispos

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Pimasertib (AS703026 or MSC1936369B) is a selective inhibitor of MEK1/2, the mitogen-activated protein kinase (MAPK) signaling pathway, which is often dysregulated in cancer cells. Pimasertib has shown potent preclinical antitumor activity and its clinical activity is being investigated in various tumor types. In this phase I study, the disposition and biotransformation of C-radiolabeled pimasertib was investigated in six patients with locally advanced or metastatic solid tumors (NCT01713036). Ultra-performance liquid chromatography-mass spectrometry and radiodetection techniques were used to investigate the profiles and structures of metabolites in plasma, urine, and feces after a single oral dose ofC-pimasertib. A total of 14 different phase I and II metabolites of C-pimasertib were detected, which were principally generated through oxidations and conjugations (direct and indirect); but other reactions included isomerization, N-dealkylation, deamination, and deiodination to form minor metabolites. Two major metabolites (>10% of total drug-related material), M554 and M445, were identified in plasma and urine. In feces, M445 was the primary metabolite with only trace amounts of M554 excreted. All other metabolites, including enantiomers of M445 and pimasertib, were detected to a lesser extent (<5%) in these matrices. M445 was identified as a carboxylic acid of pimasertib. M554 was identified as a novel phosphoethanolamine conjugate on the propanediol moiety of pimasertib by high-resolution mass spectrometry and multiple nuclear magnetic resonance spectroscopy techniques. To our knowledge, a phosphoethanolamine conjugate is a novel metabolite not previously described for a pharmaceutical agent and requires detailed further investigations to understand any implications.

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“…26,27 A unique phosphocholine ester metabolite has also been identified that shows good binding to FKBP12, but only weak inhibition of mTOR. 28 The structures of the major metabolites generated after incubation of everolimus with human liver microsomes are shown in Figure 2A. Based on the published literature, none of these metabolites seems to retain more than 10% of the immunosuppressive activity of everolimus.…”

Section: Metabolism and Eliminationmentioning

confidence: 99%

Everolimus in kidney transplantation

Cooper¹,

Christians²,

Wiseman

2011

TRRM

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Everolimus is a novel target of rapamycin (mTOR)-I analog that has recently been approved in combination with cyclosporine A and steroids for use in the prevention of organ rejection in kidney transplant recipients. Compared with rapamycin, everolimus is characterized by a shorter half-life and improved bioavailability. Prior to US Food and Drug Administration approval, a number of Phase II and III clinical trials were undertaken to evaluate the effectiveness of everolimus in combination with calcineurin inhibitors for preventing acute rejection and promoting allograft survival in kidney transplant recipients. In this report, we review the pharmacokinetic properties of everolimus, the clinical efficacy studies that led to its approval for use in kidney transplantation, as well as reported data on patient safety and tolerability associated with its use.

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The Macrolide Everolimus Forms an Unusual Metabolite in Animals and Humans: Identification of a Phosphocholine Ester

Cited by 8 publications

References 13 publications

Phosphocholine Conjugation: An Unexpected In Vivo Conjugation Pathway Associated with Hepatitis C NS5B Inhibitors Featuring A Bicyclo[1.1.1]Pentane

Phosphocholine Conjugation: An Unexpected In Vivo Conjugation Pathway Associated with Hepatitis C NS5B Inhibitors Featuring A Bicyclo[1.1.1]Pentane

Metabolism of the MEK1/2 Inhibitor Pimasertib Involves a Novel Conjugation with Phosphoethanolamine in Patients with Solid Tumors

Everolimus in kidney transplantation

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