Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: UMLS:C0393754 (
HSA
)
2,996
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
The intense intrinsic fluorescence emissions from several clinically relevant camptothecin drugs have been exploited in order to study the structural basis of drug binding to human serum albumin. Both HPLC and time-resolved fluorescence spectroscopic methodologies were employed to characterize the associations of camptothecins with
HSA
in phosphate-buffered saline (pH 7.4) at 37 degrees C. The alpha-hydroxy delta-lactone ring moiety of camptothecin (C), 10-hydroxycamptothecin (HC), 10,11-(methylenedioxy)camptothecin (MC) and 9-chloro-10,11-(methylenedioxy)camptothecin (CMC) was in each case observed to hydrolyze more rapidly and completely in the presence of
HSA
than in the protein's absence. Binding isotherms constructed by the method of fluorescence lifetime titration showed that
HSA
bound preferentially the carboxylate forms of C, HC, MC, and CMC over their lactone forms, thereby providing an explanation for the shift to the right in the lactone-carboxylate equilibrium observed for each compound upon
HSA
addition. In marked contrast, three analogues (SN-38,
CPT-11
, and topotecan) all displayed enhanced stabilities in the presence of
HSA
. While the lifetimes of
CPT-11
, topotecan, and the carboxylate forms of both drugs were insensitive to the addition of
HSA
, the lifetimes of both SN-38 and its carboxylate form did titrate upon
HSA
addition. Analysis of binding isotherms constructed for the albumin interactions of SN-38 and its carboxylate form demonstrated a higher overall association constant for the lactone form [640 (M amino acid (aa) residues)-1] relative to the carboxylate form [150 (M aa)-1]. Our studies indicate that specific modifications at the 7- and 9-positions of the quinoline nucleus, such as those contained in
CPT-11
, topotecan, and SN-38, enhance drug stability in the presence of
HSA
. In the case of SN-38, the enhanced stability was shown to be due to preferential associations between the drug's lactone form and the blood protein.
...
PMID:The structural basis of camptothecin interactions with human serum albumin: impact on drug stability. 828
The interactions of camptothecin (CPT) and its derivatives (
CPT-11
and SN-38) with human plasma proteins (serum albumin (
HSA
) and alpha 1-acid glycoprotein (alpha 1-AGP)) were studied mainly by means of ultraviolet and fluorescence spectroscopy. The binding constants of lactone ring-opened forms (A form) of CPT and
CPT-11
with
HSA
were larger than those of the intact lactone forms (L form). In the case of SN-38, there was no difference in the constants between A form and L form. The binding constant of CPT (A form) with
HSA
was larger than those of
CPT-11
and SN-38. The presence of cisplatin, which is presumed to be coadministered with CPT derivatives, did not affect the interaction of CPT derivatives with
HSA
. Only L form of
CPT-11
among the CPT derivatives examined interacted with alpha 1-AGP, followed by quenching the fluorescence of alpha 1-AGP.
...
PMID:[Interaction of camptothecin derivatives with human plasma proteins in vitro]. 848 59
