Metabolic fate of the new Ca++-channel blocking agent (+)-(2S,3S)-3-acetoxy-8-chloro-(2-(dimethylamino)ethyl)-2,3-dihydro- 2-(4-methoxyphenyl)-2,5-benzothiazepin-4-(5H)-one maleate. Distribution, excretion and protein binding in rats and dogs.
Distribution, excretion and protein binding of (+)-(2S,3S)-3-acetoxy-8-chloro-(2-(dimethylamino)ethyl)-2,3-dihydro- 2-(4-methoxyphenyl)-2,5-benzothiazepin-4-(5H)-one maleate (TA-3090) in rats and dogs were investigated after oral (30 mg/kg (rats), 2 mg/kg(dogs] and intravenous (3 mg/kg (rats), 0.2 mg/kg (dogs) administration of 14C-TA-3090. Plasma level of radioactivity in rats reached plateau (6.04 micrograms equiv. of TA-3090 free base/ml) 1 h after oral administration. The plateau level continued at least up to 6 h. The plasma concentration of the unchanged drug (free base) reached the maximum (425 ng/ml) at 45 min after oral administration, and then decreased with a half-life of 1.16 h. Plasma level of radioactivity after intravenous administration to rats rose gradually up to 1 h and thereafter it was kept constant for 6 h. Plasma concentration of the unchanged drug decreased with half-lives of 0.43 h (alpha phase) and 1.33 h (beta phase) after intravenous administration. In dogs, the peak level of plasma radioactivity after oral administration was 227 ng/ml at 1 h. The Cmax, Tmax and t1/2 of unchanged drug were 31 ng/ml, 1.34 h and 4.13 h, respectively. The plasma levels of total radioactivity and unchanged drug after intravenous administration to dogs were 146 and 142 ng/ml at 1 min, respectively. The t1/2 of the plasma radioactivity were 0.02 h (alpha) and 4.02 h (beta). Those of unchanged drug were 0.03 h (alpha) and 1.66 h (beta).(ABSTRACT TRUNCATED AT 250 WORDS)
Nakamura
S
S
Biological Research Laboratory, Tanabe Seiyaku Co., Ltd., Saitama, Japan.
Ohashi
M
M
Suzuki
T
T
Sugawara
Y
Y
Usuki
S
S
Takaiti
O
O
D000818:Animals; D001345:Autoradiography; D001646:Bile / Q000378:metabolism; D001711:Biotransformation; D002121:Calcium Channel Blockers / Q000378:metabolism* / Q000493:pharmacokinetics; D004110:Diltiazem / Q000031:analogs & derivatives*; D004285:Dogs; D004764:Enterohepatic Circulation; D005243:Feces / Q000032:analysis; D008401:Gas Chromatography-Mass Spectrometry; D008297:Male; D011485:Protein Binding; D051381:Rats; D011919:Rats, Inbred Strains; D013841:Thiazepines / Q000378:metabolism* / Q000493:pharmacokinetics; D014018:Tissue Distribution
D002121:Calcium Channel Blockers; D013841:Thiazepines; C056595:clentiazem; D004110:Diltiazem