Cisplatin half lives

Table 5.3 Cisplatin half-lives (/i for reaction with duplexes having specific binding sites and percentage of total platinated DNA adducts"...

While carboplatin has the same mechanism of action as cisplatin, it has a much less toxic side-effect profile than cisplatin. The pharmacokinetics of carboplatin are best described by a two-compartment model, with an a half-life of 90 minutes and a terminal half-life of 180 minutes. Carboplatin is eliminated almost entirely by the kidney by glomerular filtration and tubular secretion. Many chemotherapy regimens dose carboplatin based on an area under the curve (AUC), which is referred to... 

It has been postulated that carboplatin and its analogs act as prodrugs, reacting with chloride in plasma to give cisplatin. However, the rate of aquation of carboplatin is too slow to account for its in vivo activity (half-life 11 days in water), and the reactions of carboplatin with phosphate, chloride, or water are slower than direct reactions... 

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. 

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. 

The chloromonoadducts are unstable in aqueous solution and lead to intra and/or interstrand diadducts after aquation of the chloride ligand (vide infra). They can also cross-link DNA to proteins either directly or after aquation [25]. The half-life of the monoadducts formed from cisplatin and PtCl(R2-en) (with R2-en = rac-(lS,2S,4.S )-e-W-2-amino-2-(aminomethyl)-7-oxabicyclo[2.2.1]heptane) on DNA at 310K are 2 h 40 30 min and 8 h 20 20 min [49], respectively, a rather long time on the scale of cellular processing . 

Displacement of Pt-S-Bound L-Methionine by 5 -GMP. In an effort to understand why cisplatin reacts with 5 -GMP even in the presence of methionine, Barnham et al. [83] performed a competitive reaction experiment between [Pt(dien)Cl]Cl, L-methionine, and 5 -GMP. They observed that, in the first 40 hours of the reaction, the methionine was platinated to yield [Pt(dien)(Met-S )]2+, whereas only little of the 5 -GMP had reacted. In the latter stages of the reaction, this complex disappears as the platinum binds to 5 -GMP, resulting in the complex [Pt(dien)(5 -GMP, N(7))]2+ and free methionine. The kinetics of the displacement reaction were studied and the half-life of the reaction was determined to be 167 h at 310 K. The calculated 77 and. S values for this displacement reaction are indicative of a sub-... 

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],... 

Lipoplatin (Regulon Inc. Mountain View, CA, USA) is another pegylated liposomal cisplatin formulation composed of showed plasma half-life is 60-117 h in clinical study, depeuding on the dose (Boulikas et al. 2005 Stathopoulos et al. 2005). The study also found that Lipoplatin has no nephrotoxicity up to a dose of 125 mg/m every 14 days without the serious side effects of cisplatin. Clinical evaluation of pegylated liposomal... 

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). 

It should increase delivery of the bioactive moiety and decrease toxicity. In aqueous solutions, cisplatin hydrolyzes with a reaction half-life of nine hours at room temperature or 2.4 hours at 37 °C. Cisplatin hydrolyzes in the body forming a wide variety of platinum-containing agents, none of which is as active as cisplatin itself and most of which exhibit increased toxicity to the body. Formation of these hydrolysis products increases the amount of platinum complex that must be added to effect desired tumor reduction. Consequently, this increases the amount of platinum complexes that must be processed by the body. The polymeric structure should also shield the platinum moiety from unwanted hydrolysis increasing the concentration of platinum in the beneficial form that is retained in the body thus permitting lower effective doses of the drug to be used. The nature of the more hydrophobic polymer chain should also act to protect the platinum moiety from ready attack by water. 

Miller and House have studied the reactions of cisplatin in acidic and basic solution in some detail [14 ]. Although in principle cisplatin can isomerise to transplatin, the process is irrelevant under biological conditions with a half life at 37°C of 1.8 years. In acidic conditions, cisplatin hydrolyses as shown in Scheme 2. 

The cr ion concentration in blood plasma is ca. 103 mM, while the Cf concentration in the cell interior is 4 mM. As the blood plasma has pH = 7.4 a possible set of equilibria can be considered which will allow Pt transport across the cell membrane to occur. Neutral complexes will be transported across the cell wall much more readily than charged complexes. Fig. 4.17. Within the cell, cisplatin has a half life of ca. 2 hr at 37°C and gives some 50% cis-[Pt(NH3)2Cl(OH2)] and 50% c/s-[Pt(NH3)2Cl(OH)] at pH 7.4. 

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