*Present address: First Department of Clinical Pharmacy, School of Pharmaceutical Sciences, Kyusyu University of Health and Welfare, Nobeoka, Japan.
Characterization of nelfinavir binding to plasma proteins and the lack of drug displacement interactions
Article first published online: 18 JAN 2006
Volume 7, Issue 2, pages 122–128, March 2006
How to Cite
Motoya, T., Thevanayagam, L., Blaschke, T., Au, S., Stone, J., Jayewardene, A., Chi, J. and Aweeka, F. (2006), Characterization of nelfinavir binding to plasma proteins and the lack of drug displacement interactions. HIV Medicine, 7: 122–128. doi: 10.1111/j.1468-1293.2006.00356.x
- Issue published online: 18 JAN 2006
- Article first published online: 18 JAN 2006
- Received: 19 October 2004, accepted 1 March 2005
- M8 metabolite;
- plasma protein binding;
- α1-acid glycoprotein
To determine the characteristics of the binding of nelfinavir and active M8 to α1-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).
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.
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 × 107/m and 3.33 × 107/m for AAG and 1.11 × 106/m and 7.92 × 105/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.
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.