Abstract
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 β-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.
Footnotes
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Send reprint requests to: Keishi Oikawa, 1-8, Azusawa 1-Chome Itabashi-ku, Tokyo 174-8511, Japan. E-mail:oikawa{at}yamanouchi.co.jp
- Abbreviations used are::
- t-PA
- tissue-type plasminogen activator
- rwt-PA
- recombinant wild-type t-PA
- EGF domain
- epidermal growth factor domain
- CLtotal
- total clearance
- CLhepatic
- hepatic clearance
- t1/2α
- half-life in α phase
- t1/2β
- half-life in β phase
- AUC0→∞
- area under the plasma concentration-time curve from zero to infinity
- Vdss
- distribution volume at the steady state
- MRT
- mean residence time
- GFC
- gel filtration chromatography
- LUI
- liver uptake index
- Ex,drug
- extravascular hepatic extraction
- CLhepatic (LUI)
- hepatic clearance in LUI studies
- RME
- receptor-mediated endocytosis
- Received November 29, 1999.
- Accepted May 18, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
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