AbstractWe have studied the dog model for predicting the oral absorption of deramciclane, a novel anxiolytic compound, as a model acid-labile drug. The absorption profile of deramciclane was studied in man and beagle dogs after administration of conventional capsules and enteric coated tablets. Absorption in dogs pretreated with pentagastrin or saline was also studied after administration of conventional capsules. The in-vitro stability of deramciclane was determined over the pH range 1.2–6.0.The rate of degradation of deramciclane increased ten-fold as the pH was reduced from 2.1 to 1.2 (t.β (elimination half-life) 9 h and 39 min, respectively). Deramciclane was stable at pH. 3. The two formulations were bioequivalent in dogs and there were no significant differences between pharmacokinetic parameters measured for dogs pretreated with pentagastrin or saline. In man the mean relative bioavailability and Cmax (peak plasma concentration) for the conventional capsules were approximately 75% and 83% of those for the enteric coated tablets (P = 0.0004 and P = 0.0031, respectively). This was probably because of degradation of deramciclane at lower pH of man’s stomach compared with that of the dog. Pentagastrin was probably unsuccessful in reducing gastric pH and thus no change in absorption was observed.It is concluded that the absorption of deramciclane, and possibly other acid-labile drugs, cannot be predicted by use of the dog model.

01 Mar 2010·Biochimica et Biophysica Acta (BBA) - General Subjects

Selective binding interactions of deramciclane to the genetic variants of human α1-acid glycoprotein

Article

Author: Miklós Simonyi ; Júlia Visy ; Ferenc Zsila ; György Mády ; Ilona Fitos

BACKGROUNDalpha(1)-Acid glycoprotein (AGP) plays a decisive role in the serum protein binding of several drugs.Genetic variants of AGP have different ligand binding properties. The binding of deramciclane (DER), a chiral anxiolytic agent, has been studied on A and F1/S genetic variants of AGP.METHODSThe effects of DER and reference drugs on the binding of specific fluorescent and circular dichroism (CD) probes of AGP were determined. Dicumarol (DIC) binding was measured by CD and equilibrium dialysis.RESULTSDER effectively displaced probes bound to variant A, while it was less effective at displacing probes bound to variant F1/S. DER increased the binding and inverted the induced CD spectrum of DIC in the solution of variant F1/S. This phenomenon could not be brought about by the enantiomer of DER.CONCLUSIONDER has high-affinity binding (K(a)> or =2x10(6) M(-1)) to variant A, while its binding to the variant F1/S is about thirty times weaker. During simultaneous binding of DER and DIC to variant F1/S a ternary complex having about four times higher affinity is formed, in which the opposite chiral conformation of DIC is favored.GENERAL SIGNIFICANCEThe binding interactions found prove that AGP can simultaneously accommodate different ligand molecules. Even weakly bound ligands can provoke unexpected allosteric protein binding interactions.

18 Feb 2010·Journal of Pharmacy and PharmacologyQ3 · MEDICINE

Oral, Intraperitoneal and Intravenous Pharmacokinetics of Deramciclane and its N-desmethyl Metabolite in the Rat

Q3 · MEDICINE

Article

Author: Grézal, Gyula ; Bojti, Erzsébet ; Abermann, Miklós ; Nemes, Katalin Balogh ; Al-Behaisi, Samar ; Klebovich, Imre

AbstractThe pharmacokinetic properties of deramciclane fumarate (EGIS-3886), a new potential anxiolitic agent, and its N-desmethyl metabolite have been investigated in Wistar rats after 10 mg kg−1 deramciclane fumarate was administered orally, intraperitoneally or intravenously.A highly sensitive, validated and optimized gas chromatographic method with nitrogen selective detection (GC-NPD) using a solid-phase extraction technique was used to determine plasma levels of the parent compound and its N-desmethyl metabolite.After oral administration the absorption of the parent compound was very fast (tmax 0.5 h). The maximum plasma concentration (Cmax) was detected at 44.9, ≥177.8 and ≥2643.0 ng mL−1 after oral, intraperitoneal and intravenous administration of deramciclane, respectively. For the metabolite the respective Cmax values were 32.0, ≥25.4 and 51.0 ng mL−1. The pharmacokinetic curves of both the parent compound and its metabolite showed enterohepatic recirculation for all administration routes. The biological half-life (tβ1/2) for deramciclane ranged from 3.42 to 5.44 h and for the N-desmethyl metabolite the range was 2.90–5.44 h, after administration of the drug by the three different routes. After intravenous administration AUC0-∞ of deramciclane was 29.2- and 5.4-times higher than that observed after oral and intraperitoneal treatment, respectively. These AUC0-∞ ratios were only 2.1- and 1.5-times higher for the metabolite. The absolute bioavailability of deramciclane in rats was 3.42% after oral and 18.49% after intraperitoneal administration.The comparative pharmacokinetic study of deramciclane in rat after the different administration routes showed fast absorption. Furthermore, plasma levels were found to be administration route-dependent, low bioavailability of the parent compound indicated an extremely fast and strong first-pass metabolism. The apparent volume of distribution suggested strong tissue binding after administration of the drug by any of the three routes studied.

100 Deals associated with Deramciclane fumarate

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KEGG	Wiki	ATC	Drug Bank
-	Deramciclane fumarate	-	DB06512

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Indication	Highest Phase	Country/Location	Organization	Date
Anxiety Disorders	Phase 2	US	-	-
Anxiety Disorders	Phase 2	-	Pfizer Inc.	-
Anxiety Disorders	Phase 2	-	Orion Oyj	-
Anxiety Disorders	Phase 2	-	Egis Gyógyszergyár Zrt.	-
Anxiety Disorders	Phase 2	ZA	-	-
Anxiety Disorders	Phase 2	FI	Orion Oyj	-
Anxiety Disorders	Phase 2	-	-	-
Seizures	Discovery	HU	Hungarian Academy of Sciences	01 Mar 1989

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