Binding of cosalane—a novel highly lipophilic anti-HIV agent—to albumin and glycoprotein

Kuchimanchi, Kameswara R.; Ahmed, Mahmoud S.; Johnston, Thomas P.; Mitra, Ashim K.

doi:10.1002/1520-6017(200105)90:5<659::aid-jps1022>3.0.co;2-8

Cited by 15 publications

(7 citation statements)

References 21 publications

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“…Similar to many other lipophilic basic drugs [20][21][22] gefitinib was mainly bound to plasma proteins including HSA (90%) and AAG (78%). The total binding constant (nK) was estimated as 1.85 × 10 4 M −1 to HSA and 1.13 × 10 5 M −1 to AAG indicating > 6-fold higher affinity of gefitinib for AAG.…”

Section: Discussionmentioning

confidence: 99%

Binding of gefitinib, an inhibitor of epidermal growth factor receptor-tyrosine kinase, to plasma proteins and blood cells: in vitro and in cancer patients

Brahmer

Messersmith

et al. 2006

Invest New Drugs

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Gefitinib exhibits wide inter-subject pharmacokinetic variability which may contribute to differences in treatment outcome. Unbound drug concentrations are believed to be more relevant to pharmacological and toxicological responses than total drug. Thus it is desirable to determine gefitinib binding in plasma and factors affecting this process. An equilibrium dialysis method using 96-well microdialysis plates was optimized and validated for determining the fraction unbound (fu) gefitinib in human plasma. Gefitinib binding in plasma from four different species and isolated protein solutions as well as drug partitioning in human blood cells were investigated. Unbound gefitinib plasma concentrations were measured in 21 cancer patients receiving daily oral gefitinib 250 mg or 500 mg. It was found that gefitinib was extensively bound in human rat mouse and dog plasma with mean fu values of 3.4%, 3.8%, 5.1% and 6.0% respectively. In isolated protein solutions approximately 90% and 78% of gefitinib was bound to human serum albumin (HSA) (40 mg/dL) and alpha1-acid glycoprotein (AAG) (1.4 mg/dL) with binding constants of 1.85 x 10(4) M(-1) and 1.13 x 10(5) M(-1) respectively. In whole blood 2.8% of gefitinib existed as the free drug while 79.4% and 17.8% was bound to plasma proteins and blood cells respectively. In plasma from cancer patients fu at pre-treatment varied 2.4-fold (mean 3.4 +/- 0.6%; range 2.2-5.4%) and fu was constant over the 28-days of treatment (P > 0.05). Pre-treatment AAG concentration was negatively correlated with pre-treatment fu (R2 = 0.28, P = 0.01). In conclusion gefitinib is highly protein bound (approximately 97%) in human plasma. Variable AAG concentrations observed in cancer patients may affect gefitinib fu with implications for inter-subject variation in drug toxicity and response.

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Section: Discussionmentioning

confidence: 99%

Binding of gefitinib, an inhibitor of epidermal growth factor receptor-tyrosine kinase, to plasma proteins and blood cells: in vitro and in cancer patients

Brahmer

Messersmith

et al. 2006

Invest New Drugs

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“…The competition binding between SAL and cosalane to HSA was studied by a gel filtration technique, the results of this work showed that SAL reduced cosalane binding by one order of magnitude (Kuchimanchi et al, 2001). The competitive binding of ibuprofen (IBP) and SAL to HSA was also studied by using nuclear magnetic resonance (NMR) relaxation measurements.…”

Section: Competition Of Two Drugs On Hsamentioning

confidence: 99%

“…Cosalane binding to HSA was determined in the presence of salicylic acid by a gel filtration technique, which showed that cosalane and SAL could bind to HSA simultaneously (Kuchimanchi et al, 2001). Using nuclear magnetic resonance (NMR) relaxation measurements, ibuprofen (IBP) Fig.…”

Section: Coexistence Of Two Drugs In Sudlow Site 1 Of Hsamentioning

confidence: 99%

“…On the other hand, the interaction between araC and BSA was weaker in the presence of aspirin (Sulkowska et al, 2006). Over the last decade, several techniques have been developed and applied to study the drug-drug interaction on binding to serum albumin (HSA or bovine serum albumin, BSA) (Bai et al, 2005;Cui et al, 2004;Kuchimanchi et al, 2001;Sowell et al, 2001). However, there are not many detailed structural studies of such drug-drug interaction (Ghuman et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

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A new drug binding subsite on human serum albumin and drug–drug interaction studied by X-ray crystallography

Zhu

Yang

Chen

et al. 2008

Journal of Structural Biology

121

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“…A number of biophysical techniques have been used to study the interactions of ligands with albumin. These include fluorescence spectroscopy [23,24], gel chromatography [25], high-performance liquid chromatography (HPLC) [26], electrospray ionization mass spectrometry [27] and nuclear magnetic resonance (NMR). Although fluorinated natural products are relatively rare, it was reported that approximately 25% of drug molecules contain at least one fluorine atom [28].…”

Section: Introductionmentioning

confidence: 99%

Targeting the Endocannabinoid System for Neuroprotection: A 19F-NMR Study of a Selective FAAH Inhibitor Binding with an Anandamide Carrier Protein, HSA

et al. 2013

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Fatty acid amide hydrolase (FAAH), the enzyme involved in the inactivation of the endocannabinoid anandamide (AEA), is being considered as a therapeutic target for analgesia and neuroprotection. We have developed a brain permeable FAAH inhibitor, AM5206, which has served as a valuable pharmacological tool to explore neuroprotective effects of this class of compounds. In the present work, we characterized the interactions of AM5206 with a representative AEA carrier protein, human serum albumin (HSA), using 19 F nuclear magnetic resonance (NMR) spectroscopy. Our data showed that as a drug carrier, albumin can significantly enhance the solubility of AM5206 in aqueous environment. Through a series of titration and competitive binding experiments, we also identified that AM5206 primarily binds to two distinct sites within HSA. Our results may provide insight into the mechanism of HSA-AM5206 interactions. The findings should also help in the development of suitable formulations of the lipophilic AM5206 and its congeners for their effective delivery to specific target sites in the brain.

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Binding of cosalane—a novel highly lipophilic anti-HIV agent—to albumin and glycoprotein

Cited by 15 publications

References 21 publications

Binding of gefitinib, an inhibitor of epidermal growth factor receptor-tyrosine kinase, to plasma proteins and blood cells: in vitro and in cancer patients

Binding of gefitinib, an inhibitor of epidermal growth factor receptor-tyrosine kinase, to plasma proteins and blood cells: in vitro and in cancer patients

A new drug binding subsite on human serum albumin and drug–drug interaction studied by X-ray crystallography

Targeting the Endocannabinoid System for Neuroprotection: A 19F-NMR Study of a Selective FAAH Inhibitor Binding with an Anandamide Carrier Protein, HSA

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