Pharmacokinetic scaling of SJ-8029, a novel anticancer agent possessing microtubule and topoisomerase inhibiting activities, by species-invariant time methods.
This study examined the pharmacokinetic disposition of SJ-8029, a novel anticancer agent possessing microtubule and topoisomerase inhibiting activities, in mice, rats, rabbits and dogs after i.v. administration. The serum concentration-time curves of SJ-8029 were best described by tri-exponential equations in all these animal species. The mean Cl, V(ss) and t(1/2) were 0.3 l/h, 0.1 l and 63.2 min in mice, 1.5 l/h, 1.6 l and 247.7 min in rats, 13.8 l/h, 39.6 l and 245.9 min in rabbits, and 29.2 l/h, 44.6 l and 117.4 min in dogs, respectively. Based on animal data, the pharmacokinetics of SJ-8029 were predicted in humans using simple allometry and also by several species-invariant time transformations using kallynochron, apolysichron and dienetichron times. The human pharmacokinetic parameters of Cl, V(ss) and t(1/2) predicted by the simple allometry and various species-invariant time methods were 50.4-145.0 l/h, 369.0-579.8 l and 242.0-1448.3 min, respectively. These preliminary parameter values may be useful in designing early pharmacokinetic studies of SJ-8029 in humans.
Shin
Beom S
BS
College of Pharmacy, Sungkyunkwan University, Suwon, Kyonggi-do 440-746, Korea.
Kim
Dong H
DH
Cho
Chang Y
CY
Park
Si K
SK
Chung
Sun G
SG
Cho
Eui H
EH
Lee
Sun H
SH
Joo
Jeong H
JH
Kwon
Ho S
HS
Lee
Kang C
KC
Yoo
Sun D
SD
D000166:Acridines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001835:Body Weight / Q000187:drug effects; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D004285:Dogs; D006207:Half-Life; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008870:Microtubules / Q000187:drug effects* / Q000378:metabolism; D010879:Piperazines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D011237:Predictive Value of Tests; D011725:Pyridines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity; D059005:Topoisomerase II Inhibitors
C483162:4-(3,5-dimethylphenyl)piperazine-1-carboxylic acid(5-(1-(3-(acridine-9-yl-amino)-5-hydroxymethylphenylcarbamoyl)-ethylcarbamoyl)-6-ethyl-2-methoxypyridine-3-yl)amide; D000166:Acridines; D000970:Antineoplastic Agents; D010879:Piperazines; D011725:Pyridines; D059005:Topoisomerase II Inhibitors; D004250:DNA Topoisomerases, Type II