Pharmacokinetics of TDP223206 following intravenous and oral administration to intact rats and intravenous administration to bile duct-cannulated rats.
The pharmacokinetics of TDP223206 was studied following single intravenous and oral administrations in rats. A mixture of TDP223206 and (14)C-TDP223206 were administered to intact and bile duct-cannulated rats. Following intravenous administration, plasma concentrations declined biphasically. The AUC(inf) increased linearly with dose but was not dose proportional. The PK parameters of TDP223206 indicated low clearance (254-386 ml/h/kg) and a moderate volume of distribution (968-1883 ml/kg). The bioavailability was 32.95% and 24.46% for 10 and 50 mg/kg oral doses, respectively. (14)C-TDP223206 was distributed widely into different tissues with small intestine, liver, kidneys and large intestine having large tissue to plasma ratios. (14)C-TDP223206 was the major circulating component in the plasma. A total of 91.2% of administered radioactivity of (14)C-TDP223206 was recovered in bile indicating that biliary excretion was the major pathway for drug elimination. (14)C-TDP223206-acyl glucuronides were the major metabolites in bile. The oxo-(14)C-TDP223206 was the major metabolite in plasma and an important metabolite in bile. Two forms of diastereomeric acyl glucuronides of (14)C-TDP223206 were detected in bile with similar LC/MS intensities suggesting a similar biotransformation capacity. Only one form of these (14)C-TDP223206-acyl glucuronides was detected in plasma suggesting that enterohepatic recirculation was related to the nature of the stereo-isomers.
Chen
Yanmin
Y
Johnson & Johnson Pharmaceutical Research and Development LLC, Welsh and McKean Roads, Spring House, PA 19477, USA. ychen13@prdus.jnj.com
Cheng
Deping
D
Marugan
Juan Jose
JJ
Manthey
Carl
C
Tomczuk
Bruce
B
Huebert
Norman
N
D000284:Administration, Oral; D000818:Animals; D001646:Bile / Q000378:metabolism; D005243:Feces / Q000737:chemistry; D007211:Indoles / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D007275:Injections, Intravenous; D039302:Integrin alphaVbeta3 / Q000037:antagonists & inhibitors*; D008297:Male; D011422:Propionates / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution
D007211:Indoles; D039302:Integrin alphaVbeta3; D011422:Propionates; C530473:TDP223206