Dipyridamole binding to proteins in human plasma and tissue culture media.
Dipyridamole (Persantin), a commonly used coronary vasodilator and antithrombotic drug, has been intensively studied for its potential use in combination chemotherapy for cancer, and, recently, for acquired immunodeficiency syndrome. However, the strong binding of dipyridamole to proteins in human plasma complicates quantitative extrapolations from in vitro data to the clinic. To aid in such extrapolations, we incubated dipyridamole in human plasma and in tissue culture media containing 10% fetal calf serum (FCS), and determined the equilibrium levels of free drug. In human plasma, after addition of 2 to 10 mumol/L dipyridamole (i.e., in the therapeutically relevant concentration range), the fraction of free drug averaged between 1.9% and 3.5%. In 10% FCS, after addition of 0.08 to 5 mumol/L dipyridamole (i.e., the experimentally relevant concentration range), mean free fractions were in the 75% to 100% range. Relating various total dipyridamole levels in the therapeutically relevant range in human plasma to those in 10% FCS that provided identical fractions of free drug gave ratios in the 24 to 55 range. Thus, a multiplication factor in the above range is suggested for the interconversion of in vitro and in vivo dipyridamole concentrations that provide equivalent levels of free drug.
Szebeni
J
J
Theoretical Immunology Section, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
Weinstein
J N
JN
D001798:Blood Proteins / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D003470:Culture Media; D046508:Culture Techniques; D004176:Dipyridamole / Q000378:metabolism*; D005470:Fluorometry; D006801:Humans; D014462:Ultrafiltration
D001798:Blood Proteins; D003470:Culture Media; D004176:Dipyridamole