Pharmacokinetic Studies of (S)-(+)-6-(2-chlorophenyl)-3-cyclopropanecarbonyl-8, 11-dimethyl-2, 3, 4, 5-tetrahydro-8H-pyrido[4', 3':4, 5]thieno [3, 2-f] [1, 2, 4]triazolo[4, 3-a][1, 4]diazepine (E6123) (I) : Absorption, Distribution, Metabolism, Excretion and Identification of Metabolites in Beagle Dogs

Abstract

The absorption, distribution, metabolism, excretion and identification of metabolites of E6123, (S)-(+)-6-(2-chlorophenyl)-3-cyclopropanecarbonyl-8, 11-dimethyl-2, 3, 4, 5-tetrahydro-8H-pyrido [4', 3' : 4, 5]thieno[3, 2-f][1, 2, 4]triazolo[4, 3-a][1, 4]diazepine, were studied in beagle dogs after a single oral administration.
1. After oral administration, the radioactivity in the blood, plasma and hematocytes reached their C_maxs at 2.3h, 3.0h and 2.0h, respectively. And then the radioactivity decreased two-exponentially with their t_1/2^λ₁ and t_1/2 of 6.3h and 33.9h in blood, 4.9h and 38.7h in plasma, 3.0h and 18.7h in hematocytes, respectively. The AUCs in blood, plasma and hematocytes were 3952, 3745, 4167ng eq. ·h/ml, respectively.
2. After oral administration, C_max of unchanged drug in plasma was reached at 1.3h and then decreased rapidly with t_1/2 of 1.7h. The AUC was 330ng·h/ml.
3. In vitro plasma protein binding of ¹⁴C-E6123 varied from 57 to 59% at the range of concentration from 10 to 1000ng/ml. After oral administration, the in vivo plasma protein binding of radioactivity was approximately 59 and 85% for plasma samples collected at 0.75 and 8h, respectively.
4. After oral administration, the radioactivity in almost all tissues were the same or higher than that of plasma ; indicating that ¹⁴C-E6123 had an increased high affinity for tissues. The radioactivity in the tissues, except eye, disappeared fastly.
5. The level of radioactivity in the lung as the target organ was 1.8 times higher than that in plasma at 2h after administration. And more, the composition of metabolites of E6123 in plasma and lung was almost the same and the unchanged drug was a main compound.
6. Approximately 42 and 47% of radioactivity was excreted in urine and feces during 48h after oral administration, respectively. At least, seven metabolites were found in urine and feces respectively, with a minor quantities of unchanged drug.
7. Main metabolic pathways were shown to be as follows ; (1) oxidation of methyl group at the 11-position (M1B), (2) oxidation of carbon 2 and (3) hydrolysis of side chain (M3). After the oxidation of carbon 2, M1A was formed. And then M1A was metabolized to M2 by reduction and to M4 by oxidation.