Liver blood flow as a major determinant of the clearance of recombinant human tissue-type plasminogen activator.
The influence of changes in liver blood flow on the clearance of rt-PA was studied both in healthy subjects and in a perfused rat liver model. Liver blood flow in healthy subjects was documented indirectly by the clearance of indocyanine green (ICG). Exercise reduced liver blood flow on average by 57% with a 95% confidence interval (95% CI) ranging from 51% to 62% (n = 5) and increased plasma levels of rt-PA activity (after an i.v. infusion of 18 mg of rt-PA over 120 min) by 119% (95% CI, 58%-203%) and rt-PA antigen by 91% (95% CI, 30%-140%). In the perfused rat liver model it was shown that halving or doubling of the physiological flow rate of a perfusate, containing rt-PA caused a proportional change in the clearance of rt-PA, while the extraction of rt-PA by the liver remained similar. In conclusion, liver blood flow is a major determinant of the clearance of rt-PA. This may have important implications for dosage of rt-PA in patients with myocardial infarction.
de Boer
A
A
Centre for Human Drug Research, University Hospital Leiden, The Netherlands.
Kluft
C
C
Kroon
J M
JM
Kasper
F J
FJ
Schoemaker
H C
HC
Pruis
J
J
Breimer
D D
DD
Soons
P A
PA
Emeis
J J
JJ
Cohen
A F
AF
D000328:Adult; D000818:Animals; D015444:Exercise / Q000502:physiology; D006801:Humans; D007208:Indocyanine Green; D007262:Infusions, Intravenous; D008102:Liver Circulation / Q000502:physiology*; D008297:Male; D008657:Metabolic Clearance Rate; D010477:Perfusion; D051381:Rats; D011919:Rats, Inbred Strains; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*
D010959:Tissue Plasminogen Activator; D007208:Indocyanine Green