Pharmacokinetic properties of TDP4815 after single intravenous and oral administrations to rat, rabbit, monkey, dog and in vitro drug metabolism.
The pharmacokinetics of TDP4815 was evaluated in rats, rabbits, dogs and monkeys. After intravenous administration, TDP4815 achieved C(O) of 3255 ng/ml in rats at 5 mg/kg, 9066 ng/ml in rabbits and 7858 ng/ml in monkeys at 6 mg/kg, and 4457 ng/ml in dogs at 3 mg/kg. The clearance (C(L)) was 3105, 1692, 835 and 640 ml/h/kg in rats, rabbits, monkeys and dogs, respectively. The volume of distribution (V(Z)) was more than 3861 ml/kg in all species, except 1915 ml/kg in monkeys. The oral bioavailability was rabbit >rat> monkey compared at 100 mg/kg, but it was much higher in dogs (>64%) after oral administrations. The calculated intrinsic clearance data suggested that the clearance of dog and human was restricted by binding to the plasma protein, and the clearance of rat and monkey was dependent on both the free fraction of plasma protein binding and the liver blood flow rate. The unbound hepatic intrinsic clearance of monkey was close to its C(L) suggesting that the hepatic clearance was an important excretion in monkeys. The poor oral bioavailability in the monkey may be related to the extensive glucuronidation. The V(Z).kg and C(L).kg in test species showed good correlation with the animal body weights (R(2)=0.87 and 0.96).
Chen
Yanmin
Y
Johnson & Johnson Pharmaceutical Research and Development, Welsh & McKean Roads, Spring House, PA 19477, USA. ychen13@prdus.jnj.com
Cheng
Deping
D
Tio
Cesar
C
Kagan
Natashia
N
Eisennagel
Stephen
S
Dasgupta
Malini
M
Tomczuk
Bruce
B
Bone
Roger
R
Huebert
Norman
N
D000284:Administration, Oral; D000818:Animals; D000925:Anticoagulants / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001682:Biological Availability; D001835:Body Weight; D004285:Dogs; D020719:Glucuronides / Q000378:metabolism; D019791:Guanidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D006801:Humans; D066298:In Vitro Techniques; D007275:Injections, Intravenous; D008099:Liver / Q000098:blood supply / Q000378:metabolism; D008252:Macaca fascicularis; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D011485:Protein Binding; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity; D014018:Tissue Distribution
C530122:(1-((5-methyl-3-(2-methylsulfonylphenylsulfonyloxy)phenoxyl)methyl) cyclopropylmethoxy)guanidine hydrochloride; D000925:Anticoagulants; D020719:Glucuronides; D019791:Guanidine