Plasma proteins cisplatin binding

Cisplatin shows biphasic plasma decay with a distribution phase half-life of 25 to 49 minutes and an elimination half-life of 2 to 4 days. More than 90% of the drug is bound to plasma proteins, and binding may approach 100% during prolonged infusion. Cisplatin does not cross the blood-brain barrier. Excretion is predominantly renal and is incomplete. 

Tissue distribution is similar to that seen with cisplatin with the highest concentrations of platinum in the kidney, liver, skin and tumors [53]. Tissue platinum concentrations were generally 0.5 to 3 fold greater than those observed after cisplatin. However, once platinum is bound to plasma protein its cytotoxicity is substantially reduced [54]. In contrast to the extensively protein binding of cisplatin, carboplatin is only 15 to 25% bound during the initial hours following administration. Renal clearance appears to be the main route... 

The in vitro interactions of the cysteine-rich intracellular protein Zn7-metal-lothionein with cisplatin and transplatin and the histidine-rich proteins Hpni32,i33 HspA with a bismuth antiulcer compound were investigated, respectively. These kinds of interactions may play a crucial role in the metabolism of various metallodrugs. Notably, drug binding to plasma proteins has a strong influence on their biodistribution, biotransformation, and pharmacokinetics, and therefore merits further characterizations. 

In human plasma at 37°, the disappearance of cisplatin occurred with a tl/2 value of 1.3 h. Kinetics analysis demonstrated that the major components of reaction were formation of hydrated species (tl/2 3.4 h), irreversible binding to proteins (t1/2 2.1 h), and formation of mobile conjugates (e.g., with glutathione t1/2 24 h) [185], A very large quantity of relevant data are compiled in [181],... 

Carboplatin (Paraplatin) is an analogue of cisplatin. Its plasma half-life is 3 to 5 hours, and it has no significant protein binding. Renal excretion is the major route of drug elimination. 

Cisplatin is able to bind to a number of extra- and intracellular proteins. Most of the platinum (65-98%) in blood plasma is protein-bound one day after rapid intravenous infusion of cisplatin [46]. H NJ-NMR spectroscopy can be used to study binding sites of Ptn ammines and amines on these proteins, such as albumin and serum transferrin. 

Solutions of cisplatin are usually given in physiological saline (NaCl), since hydrolysis reactions occur that can modify the nature of the compound and its reactions in vivo (see below). Cisplatin is rapidly cleared from the plasma after injection, 70-90 percent of the platinum being removed within the first 15 minutes. It has been found that more than half the platinum binds to serum proteins and is excreted. Most of the platinum exits the body via the urine within a few days. These results account for the use of multiple-dose chemotherapy at inter-... 

Albumin is one of the most abundant proteins in plasma ( 0.63 mM) and it is reasonable to assume that any injected metallodrug will present certain interactions with this macromolecule, which could largely determine its bioavailability and toxicology [42]. A comprehensive study of the reactions of the N-labeled cisplatin with intact and chemically modified recombinant human albumin (rHA) as well as human serum album (HSA) has been performed by ID H and [ H, Nj 2D HSQC NMR spectroscopy [53]. Recombinant albumin is similar to serum albumin but has a higher thiol content ( 0.9 -SH per rHA and only 0.4-SH per HSA) and is structurally more homogeneous. NMR studies showed that the major sulfur-containing binding site involves Met in the form of an S, N chelate but not Cys-34, which is commonly believed to be the major platination site of HSA (Scheme 5.4) [73]. 

These are also die major frictors involved in acquired resistance to cisplatin (7,8). Hie genoal phaimacokinetic principle is diat free unbound drug is the active principle, allowing distribution to tissue. Thus an important parameter in general is tissue availability - stability in plasma and protein binding may be manipulated by qiprtqiriate formuladon and liposomes and other mediods of formulation have n used (3). 

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