Determination of Novel Synthetic 5HT2C Agonist KOPC20010 by Gas-Chromatography/Mass Spectrometry and its Bioavailability in Sprague-Dawley Rats = Determination of Novel Synthetic 5HT2C Agonist KOPC20010 by Gas-Chromatography/Mass Spectrometry and its Bioavailability in Sprague-Dawley Rats

다국어 초록 (Multilingual Abstract)

5HT2C receptor among fourteen 5-HT subtypes plays important roles in several disorders such as depression, anxiety, epilepsy, schizophrenia and sleep disorders. The purpose of the study is to investigate pharmacokinetic parameters and bioavailability of a newly synthesized selective agonist of 5-HT2C receptor, KOPC-20010 (KP10) in rats after intravenous and oral administration for the development of therapeutic anti-obesity agents. KP10 was administered orally (40 mg/kg) or intravenously (20 mg/kg), blood was collected via a catheter, and analyzed by GC/MSD. The calibration curve of KP10 in plasma and urine showed high linearity (r2>0.999). The retention times of KP10 in plasma and urine were 8.7 and 9.7 min, respectively. After oral administration of 40 mg/kg, pharmacokinetic parameters were calculated as follows; Cmax value was 1242.9±1195.5 ng/mL at 1.1±0.6 hr (Tmax). AUC0->24hr and AUC0->∞ were 8034.2±960.7 and 10464.1±681.5 ng·hr/ mL, respectively. The terminal half-life was 21.9±7.6 hr. AUC0->24hr and AUC0->∞ were 4292.4±523.0 and 6111.2±756.2 ng·hr/mL, respectively, after 20 mg/kg of intravenous administration. The terminal half-life after intravenous administration was 25.1±9.4 hr. Bioavailability of KP10 was determined to 86%. The excretion amount into the urine within 48 hr was approximately 4.7 to 6.7% of the dose administered. These data may be beneficial to the anti-obesity drug development of KP10.

참고문헌 (Reference)

1 Frank M.G, "Sleep and sleep homeostasis in mice lacking the 5-HT2c receptor" 27 : 869-873, 2002

2 Millan M.J, "Serotonin 5-HT2c receptors as a target for the treatment of depressive and anxious states: focus on novel therapeutic strategies" 60 : 441-460, 2005

3 Halford J.C.G, "Serotonergic drugs effects on appetite expression and use for the treatment of obesity" 67 : 27-55, 2007

4 Issac M, "Serotonergic 5-HT2C receptors as a potential therapeutic target for the design of antiepileptic drugs" 5 : 59-67, 2005

5 Dunlop J, "Pharmacological Profile of the 5-HT2C Receptor Agonist WAY-163909; Therapeutic Potential in Multiple Indications" 12 (12): 167-177, 2006

6 Hye-Yeon Im, "Pharmacokinetics and Bioavailability of New Synthetic 5-HT2C Agonists, KKHQ80109 and KKHQ80114, in Sprague-Dawley Rats" 한국약제학회 39 (39): 327-331, 2009

7 Tecott L.H, "Mouse genetic approaches to feeding regulation: serotonin 5-HT2C receptor mutant mice" 8 : 584-588, 2003

8 Thomsen W.J, "Lorcaserin, a novel selective human 5- Hydroxytryptamine2C Agonist: in vitro and in vivo pharmacological characterization" 325 : 577-587, 2008

9 Hoyer D, "Internation Union of Pharmacology classification of receptors for hydroxytryptamine (serotonin)" 46 : 157-204, 1994

10 DiPiro J.T, "Half-life, elimination rate and AUC: In Concept in Clinical Pharmacokinetics (4th Ed.)" American Society of Health-System Pharmacists 29-44, 2005

11 Tecott L.H, "Eating disorders and epilepsy in mice lacking 5-HT2c serotonin receptors" 374 (374): 542-546, 1995

12 Giovanni G. Di, "Central serotoinin 2C receptor: from physiology to pathology" 6 : 1909-1925, 2006

13 Hoyer D, "5-HT receptor classification and nomenclature: towards a harmonization with the human genome" 36 : 419-428, 1997