Comparison of drug disposition between wild-type and novel tissue-type plasminogen activator pamiteplase in rats

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 beta-phase and total clearance after administration of (125)I-labeled pamiteplase ((125)I-pamiteplase) to rats were 480 and 22% of those of (125)I-labeled rwt-PA ((125)I-rwt-PA), respectively. The amount of radioactivity distributed in the liver after administration of (125)I-pamiteplase was lower than that of (125)I-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 (125)I-pamiteplase was markedly lower than that of (125)I-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 (125)I-pamiteplase in the liver was inhibited by rwt-PA, suggesting that there is a common uptake mechanism for both compounds.