PROTEIN-BINDING OF BREQUINAR IN THE PLASMA OF HEALTHY DONORS AND CANCER-PATIENTS AND ANALYSIS OF THE RELATIONSHIP BETWEEN PROTEIN-BINDING AND PHARMACOKINETICS IN CANCER-PATIENTS
Syp. King et al., PROTEIN-BINDING OF BREQUINAR IN THE PLASMA OF HEALTHY DONORS AND CANCER-PATIENTS AND ANALYSIS OF THE RELATIONSHIP BETWEEN PROTEIN-BINDING AND PHARMACOKINETICS IN CANCER-PATIENTS, Cancer chemotherapy and pharmacology, 35(2), 1994, pp. 101-108
The protein binding of weakly acidic and basic drugs has been shown to
be altered in cancer patients. Brequinar is a weakly acidic, low-clea
rance, and highly protein-bound (> 98% bound) antitumor agent. The pha
rmacokinetic parameters of brequinar are subject to large interpatient
variability. This large interpatient variability may be related to br
equinar's plasma protein-binding capacity (assuming no change in the i
ntrinsic clearance of the unbound drug). The objectives of this study,
therefore, were (a) to characterize brequinar's protein binding in th
e plasma of healthy donors and cancer patients and (b) to examine the
relationships between brequinar's plasma protein binding and its pharm
acokinetics in patients. Brequinar protein binding was determined in h
uman serum albumin (HSA) solution, drug-free donor plasma, and brequin
ar-free, predose plasma samples obtained from a phase I cancer trial.
Pharmacokinetic results from this study were used to examine relations
hips between plasma protein binding and drug disposition. In HSA solut
ion and healthy donor plasma, brequinar's protein binding as determine
d using spiked samples was concentration-dependent. The unbound brequi
nar fraction increased by a factor of 3 (from 0.3% to 0.9% free) in 4%
HSA solution and by a factor of 4 (from 0.4% to 1.6% free) in donor p
lasma as the brequinar concentrations increased from 0.1 to 2.3 mM in
the HSA solution and from 0.076 to 1.5 mM in the donor plasma. Analysi
s of brequinar binding characteristics using the binding ratio and Ros
enthal binding plots showed that albumin was the primary protein for b
requinar binding in human plasma. The addition of various concentratio
ns of alpha(1)-acid glycoprotein to 4% HSA solution did not affect the
protein binding of brequinar to HSA. The protein binding determined i
n the plasma of cancer patients was not quantitatively different, exce
pt for variability, from that observed in the plasma of healthy donors
. Examination of relationships between the unbound brequinar fraction
and pharmacokinetics suggested that plasma protein binding was not a m
ajor determinant of brequinar disposition in cancer patients.