Cisplatin plasma protein

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 platinium in the kidney, liver, skin and tumors [53]. Tissue platinium concentrations were generally 0.5 to 3 fold greater than those observed after cisplatin. It has been demonstrated that platin which is bound to plasma protein looses most of its cytotoxicity [54]. In contrast to cisplatin, which is extensively protein bound, carboplatin appears to be less extensively bound [15 to 25%] at least in the initial hours following administration. Renal clearance appears to be the main route of excretion, and urinary excretion of carboplatin is more rapid than that of cisplatin in animals [55] and cancer patients [56]. 50 to 80% of the dose administered is excreted in the urine over the first 24 hours [57,58,59]. It has been postulated that repeated administration of cisplatin may cause decreased carboplatin renal clearance and enhanced toxicity [60]. Renal clearance and total body clearances are reduced in patients with reduced renal function [61, 62, 63]. 

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... 

Because carboplatin is much less reactive than cisplatin, the majority of drug in plasma remains in its parent form, unbound to the proteins. Most drug is eliminated via renal excretion, with a half-life in plasma of about 2 hours. A small fraction of platinum does become irreversibly bound to plasma proteins and disappears slowly, with a half-life of 5 days or more. 

Carboplatin and cyclophosphamide are indicated in the treatment of advanced ovarian carcinoma. Cisplatin and carboplatin produce predominantly interstrand DNA crosslinks rather than DNA-protein cross-links, and the effect is cell-cycle nonspecific. Carboplatin is not bound to plasma proteins, whereas platinum from carboplatin becomes bound to plasma protein and is eliminated slowly with a half-life of 5 days. The major route of elimination of carboplatin is the kidneys, and its doses should be reduced in renal impairment. Furthermore, the coadministration of aminoglycosides increases the chance of nephrotoxicity. Carboplatin causes anemia, neutropenia, leukopenia, and thrombocytopenia requiring transfusions. Cisplatin and, to a lesser extent, carboplatin cause emesis, which requires treatment with antiemetic agents. Alopecia, pain, and asthenia do occur (see also Figure 15). 

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. 

Cisplatin cannot be administered orally because stomach acid would cause its hydrolysis. It bonds to plasma protein. The kidneys eliminate about 30-70% of the original complex. The rest is transported by the blood stream through cell membranes of different organs and tumor cells. The complex hydrolysis is rather fast because of the low chloride concentration in the intracellular region. Therefore, the platinum complex in the cell is partly in aqua form (about 40% as [c(5-Pt"(NH3)2Cl(H20)] ). The aqua complex is kinetically labile since the coordinated water is weakly bonded, compared to Cl . In addition, when the Cl leaves the complex, its increased positive charge is likely to promote... 

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. 

Of the platinum-based drugs, cisplatin or cf -diarnmincdichloroplatinum (II) has been the most studied in treatments of cancerous tumours. Quantities of the drug administered in treatments must be carefully controlled because of appearances of side effects, primarily nephrotoxicity and nausea in patients. In some studies, ultrafilterable cisplatin, or free platinum in blood serum or plasma has been differentiated from platinum bound to proteins (Goel et al., 1990). HPLC has been used extensively in separations of intact cisplatin from other species. An anion-exchange column was connected to a post-column reactor and a UV-spectrophotometer for measurements of cisplatin concentrations in plasma and urine (Kizu et al., 1995). The detection limit was 20 nmol dm-3. Modes of action... 

The level of pentosidine of nondiabetic pulmonary cancer patients in treatment with the antineoplastic drug, cisplatin, has been found to be higher than in healthy subjects,443 when the protein from urine, plasma, and erythrocyte membranes was examined by HPLC. Urine pyrraline was unaffected. This work implies a whole field of study of the interactions of medication with the Maillard reaction. 

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. 

Conversely, in another experiment using oral doses of 20, 50, 100 and 200 mg/kg to Balb C mice, broadly linear pharmacokinetics were observed. The maximum platinum levels in plasma were observed between 30 and 120 min and were delayed with increasing dose. Platinum unbound to proteins was detectable up to 7 hpost dosing. Elimination of total platinum was biphasic with a terminal half-life of 30 h. The half-life for ultrafilterable free platinum ranged from 87 to 135 min which is considerably longer than the 10 min reported for cisplatin or 25 min reported for carboplatin [25],... 

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-... 

---