Vol. 28, Issue 9, 1087-1093, September 2000

   Comparison of Drug Disposition between Wild-Type and Novel Tissue-Type Plasminogen Activator Pamiteplase in Rats

Keishi Oikawa, Takashi Watanabe, and Saburou Higuchi

Drug Metabolism Laboratories, Yamanouchi Pharmaceutical Co., Ltd., Tokyo, Japan

The pharmacokinetics of pamiteplase in rats was compared with the pharmacokinetics of recombinant wild-type tissue-type plasminogen activator (rwt-PA). The half-life in the -phase and total clearance after administration of ¹²⁵I-labeled pamiteplase (¹²⁵I-pamiteplase) to rats were 480 and 22% of those of ¹²⁵I-labeled rwt-PA (¹²⁵I-rwt-PA), respectively. The amount of radioactivity distributed in the liver after administration of ¹²⁵I-pamiteplase was lower than that of ¹²⁵I-rwt-PA; consequently, a possible difference in metabolism between the drugs was assessed by an integration plot and a tissue-sampling single-injection technique. Use of these two methods revealed that the hepatic clearances of both compounds accounted for almost all of the total clearance and also revealed that the hepatic clearance of ¹²⁵I-pamiteplase was markedly lower than that of ¹²⁵I-rwt-PA. Therefore, the lower distribution of pamiteplase in the liver compared with rwt-PA is thought to contribute greatly to the higher plasma concentration of pamiteplase. Additionally, the uptake of ¹²⁵I-pamiteplase in the liver was inhibited by rwt-PA, suggesting that there is a common uptake mechanism for both compounds.