title: Pharmacokinetics of the Experimental Non-Nucleosidic DNA Methyl Transferase Inhibitor N-Phthalyl-L-Tryptophan (RG 108) in Rats.
abstract: DNA methyl transferase (DNMT) inhibitors can re-establish the expression of tumour suppressor genes in malignant diseases, but might also be useful in other diseases. Inhibitors in clinical use are nucleosidic cytotoxic agents that need to be integrated into the DNA of dividing cells. Here, we assessed the in vivo kinetics of a non-nucleosidic inhibitor that is potentially free of cytotoxic effects and does not require cell division. The non-specific DNMT inhibitor N-phthalyl-L-tryptophan (RG 108) was injected subcutaneously in rats. Blood was drawn 0, 0.5, 1, 2, 4, 6, 8 and 24 hr after injection and RG 108 in plasma was measured by high-performance liquid chromatography coupled to mass spectrometry. Trough levels and area under the curve (AUC) were significantly higher with multiple-dose administration and cytochrome inhibition. In this group, time to maximal plasma concentration (tmax , mean ± S.D.) was 37.5 ± 15 min., terminal plasma half-life was approximately 3.7 h (60% CI: 2.1-15.6 h), maximal plasma concentration (Cmax) was 61.3 ± 7.6 μM, and AUC was 200 ± 54 μmol·h/l. RG 108 peak levels were not influenced by cytochrome inhibition or multiple-dose administration regimens. Maximal tissue levels (Cmax in μmol/kg) were 6.9 ± 6.7, 1.6 ± 0.4 and 3.4 ± 1.1 in liver, skeletal and heart muscle, respectively. We conclude that despite its high lipophilicity, RG 108 can be used for in vivo experiments, appears safe and yields plasma and tissue levels in the range of the described 50% inhibitory concentration of around 1 to 5 μM. RG 108 can therefore be a useful tool for in vivo DNMT inhibition.
authors.affiliation: Department of Experimental Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.|DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Hamburg, Germany.|Department of Cardiovascular Surgery, University Heart Center, Hamburg, Germany.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Schneeberger
authors.affiliation: Department of Experimental Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.|DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Hamburg, Germany.|Genome Institute of Singapore, Singapore.
authors.forename: Justus
authors.initials: J
authors.lastname: Stenzig
authors.affiliation: Institute of Food Chemistry, University of Münster, Münster, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Hübner
authors.affiliation: DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Hamburg, Germany.|Department of Cardiovascular Surgery, University Heart Center, Hamburg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Schaefer
authors.affiliation: DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Hamburg, Germany.|Department of Cardiovascular Surgery, University Heart Center, Hamburg, Germany.
authors.forename: Hermann
authors.initials: H
authors.lastname: Reichenspurner
authors.affiliation: Department of Experimental Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.|DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Hamburg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Eschenhagen
mesh_terms: D000818:Animals; D019540:Area Under Curve; D002851:Chromatography, High Pressure Liquid; D015254:DNA Modification Methylases / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics*; D006207:Half-Life; D020128:Inhibitory Concentration 50; D007279:Injections, Subcutaneous; D008297:Male; D013058:Mass Spectrometry; D010797:Phthalimides / Q000008:administration & dosage / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors; D014364:Tryptophan / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics
chemical_list: D004791:Enzyme Inhibitors; D010797:Phthalimides; C503639:RG108; D014364:Tryptophan; D015254:DNA Modification Methylases