Characterization of nelfinavir binding to plasma proteins and the lack of drug displacement interactions.
OBJECTIVE
To determine the characteristics of the binding of nelfinavir and active M8 to alpha1-acid glycoprotein (AAG) and human serum albumin (HSA), and to examine the displacement effects of drugs binding extensively to AAG (ritonavir and saquinavir) or to HSA (salicylic acid and valproic acid).


METHODS
Free drugs were separated by equilibrium dialysis after incubation with human plasma or purified plasma proteins and after co-incubation with potential displacers. Association constants were estimated from double-reciprocal plots of the data.


RESULTS
Nelfinavir and M8 free fractions [fractions of unbound drug (fus)] were 0.42+/-0.08% (mean+/-standard deviation) and 0.64+/-0.07%, respectively. For the two analytes, respectively, association constants were 7.25 x 10(7)/m and 3.33 x 10(7)/m for AAG and 1.11 x 10(6)/m and 7.92 x 10(5)/m for HSA. Nelfinavir fu in an AAG solution was significantly (P < 0.01) increased by the addition of ritonavir or saquinavir, whereas it was unaltered by addition of these drugs to whole plasma. Similarly, fu in an HSA solution was significantly increased (P < 0.01) by the addition of salicylic acid or valproic acid, whereas there was no difference in the free fraction in plasma.


CONCLUSIONS
The affinity of nelfinavir for human plasma proteins was higher than that of M8, and both nelfinavir and M8 showed higher affinity to AAG than to HSA. The free fraction of nelfinavir was not affected by drugs that bind extensively to AAG or albumin when these drugs were added to whole plasma in combination, suggesting a compensatory effect of alternate binding proteins.
Motoya
T
T
Department of Clinical Pharmacy, University of California at San Francisco, San Francisco, CA 94143-0622, USA.
Thevanayagam
L N
LN
Blaschke
T F
TF
Au
S
S
Stone
J A
JA
Jayewardene
A L
AL
Chi
J
J
Aweeka
F T
FT
D001667:Binding, Competitive; D001798:Blood Proteins / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D017320:HIV Protease Inhibitors / Q000097:blood*; D006801:Humans; D066298:In Vitro Techniques; D019888:Nelfinavir / Q000031:analogs & derivatives / Q000097:blood*; D009961:Orosomucoid / Q000378:metabolism; D011485:Protein Binding; D012709:Serum Albumin / Q000378:metabolism
D001798:Blood Proteins; D017320:HIV Protease Inhibitors; D009961:Orosomucoid; D012709:Serum Albumin; C495123:hydroxy-t-butylamidenelfinavir; D019888:Nelfinavir