Structural changes in albumin are a possible mechanism for fluctuation of cefazorin and ibuprofen plasma protein binding in rats with carcinogen-induced osteosarcoma.

OBJECTIVE

It is known that the protein-unbound fraction (fp) of warfarin fluctuates in the plasma of cancer patients and the fluctuation of fp is correlated with albumin concentration. However, this mechanism remains unclear. The present study was performed with the objective of elucidating variations in the protein-binding rate of specific drugs in the presence of cancer, as well as the mechanisms involved.

METHODS

Experiments were performed using Fisher 344 model rats, that we have used in previous studies. A single i.v. injection of cefazolin (CEZ) 20 mg/kg or ibuprofen (IB) 10 mg/kg was administered to both tumor-bearing and control groups. We compared relevant pharmacokinetics. Purified albumin was checked for purity with SDS-PAGE and was used in experiments on protein binding of CEZ and IB.

RESULTS

The fp of CEZ in plasma from the tumor-bearing group increased approximately 2.9-fold and the fp of IB also increased about 2.7-fold. For that reason, we purified albumin from plasma and examined its spectroscopic signature. We showed that conformational changes (i.e., decreases in the hydrophobic region, increases in endogenous tryptophan fluorescence intensity and decrease in α-helical content) had occurred in albumin in the tumor-bearing group.

CONCLUSIONS

In the present study, we confirmed that, in a state of cancer morbidity, fp was elevated for site I high-affinity CEZ and site II high-affinity IB. Moreover, our findings indicated that, as a cause of those elevations, a decrease in the albumin concentration and conformational changes due to an oxidation are involved.