Medical Pharmacology Chapter 33-34: Anticancer Drugs
Classification: Platinum Analogs:
Carboplatin (Paraplatin): Overview
Carboplatin (Paraplatin) is classified as a second-generation platinum drug that exhibits the same cytotoxic mechanisms, resistance mechanisms and general clinical pharmacology as has been described for cisplatin.3
Carboplatin also shows activity against many types of solid tumors.
One major difference compared to cisplatin is that carboplatin is associated with notably reduced gastrointestinal and kidney toxicity.
The primary dose-limiting toxic reaction to carboplatin is myelosuppression.3
Accordingly, carboplatin has been used in management of refractory blood cancers as part of transplant protocols.
Because of reduced renal toxicity potential, carboplatin does not require the aggressive intravenous hydration previously described for cisplatin and is therefore more easily administered to patients.
In a number of combination chemotherapy protocols carboplatin has replaced cisplatin.3
Mechanism of Action:
Cisplatin (Platinol), as well as carboplatin and oxaliplatin initiate their cytotoxic activity by first entering cells by means of a high affinity Cu2+ CTR1 transporter.1
Degraded transporter activity is associated with transporting these agents.
The compounds are extruded from cells by other copper transporters, in this case exporters.1
These "exporters" are ATP7A and ATP7B.
Clinical resistance to the action of these platinum-based antineoplastic drugs depends in part on the expression level of these transporters.
Once inside the cell, specific ligands associated with the platinum drugs are displaced by water which results in a positively charged molecule, highly reactive with DNA and proteins.1
Cisplatin is perhaps the most prominent organoplatinum anticancer agent.
As such, this drug has an electron-deficient metal atom (platinum) which is attractive for electron-rich DNA nucleophiles..7
As noted earlier, organoplatinum antineoplastic drugs exhibit bifunctionality given that they can accept electrons from to DNA nucleophiles.
Cross-linking with interstrand is most likely between adjacent guanine residues (diguanosine dinucleotides, about 60% in frequency) or between adenine in guanine adjacent residues (about 27% in frequency).
Cross-linking between DNA strands (interstrand) occurs much less frequently than intrastrand cross-linking.7
Cisplatin aquation is more likely to occur intracellularly and in urine due to low chloride concentration.1
By contrast, high concentrations of chloride tend to stabilize the drug, finding consistent with the observation that cisplatin-induced nephrotoxicity is prevented by chloride diuresis.
As noted earlier, formation of DNA-platinum adducts inhibit both transcription and replication.1
These adducts induce single-and double-stranded breaks as well as miscoding.
If the adducts in DNA are so recognized by p53 and other checkpoint proteins, programmed cell death or apoptosis is induced.
Various platinum analogues are different with respect to adduct configuration and adduct effects on DNA structure and function.1
For example, carboplatin (Paraplatin) and oxaliplatin (Eloxatin) form adducts more slowly compared to cisplatin.
Absorption, distribution, Metabolism Excretion: Carboplatin
Primary differences in pharmacokinetics comparing cisplatin and carboplatin is based on relatively slower conversion of carboplatin to reactive forms.8
This relative carboplatin stability is responsible for substantially reduced nephrotoxicity, compared to cisplatin,.8
Following infusion, carboplatin is readily available to tissues and exhibits plasma stability.
About 25% of an administered carboplatin dose was plasma protein associated at the four hour mark following infusion.
Disappearance of platinum (i.e. carboplatin) from plasma following infusion is described by a biphasic or triphasic curve. 8
t1/2 for the first phase is in the range of 10-100 min..
t1/2 for the second phase has been estimated at 1.3 to 1.7 hours.
Terminal phase half-time is about 10-40 hours.8
Carboplatin is mainly excreted by the kidney and exhibits a urinary excretion percentage of about 50% to 80%, primarily as parent drug, carboplatin.
About 4% appears as platinum within 1-4 days.
Carboplatin renal clearance is closely correlated with the glomerular filtration rate (GFR). Carboplatin-dosing, therefore, can be individualized, based on the patient's GFR.8
Carboplatin volume of distribution (VD) is about 16L.9
Carboplatin itself is not associated with protein binding; however, platinum derived from carboplatin binds irreversibly to plasma protein.
Carboplatin is metabolized by the liver to a very limited extent to aquated and hydroxylated derivatives.9
Carboplatin and cisplatin have been judged comparably effective in treating certain patients such as those with:1
Suboptimally surgically debulked ovarian cancer
Extensive, high-stage small cell lung cancer and
Non-small cell lung cancer.1
However, cisplatin is more likely to be effective compared to carboplatin in those patients with esophageal cancer, head and neck cancer and germ cell cancer.1
Some patients are not able to tolerate cisplatin due to renal toxicity, refractory nausea, neuropathy or ototoxicity.
In these patients, carboplatin represents a reasonable alternative for responsive tumors.
Carboplatin may be employed in high-dose treatment associated with bone marrow or peripheral stem cell rescue.1
Carboplatin exhibits a dose-limiting toxicity of myelosuppression expressed mainly as thrombocytopenia.
Carboplatin administration may also induce a hypersensitivity reaction which may be manageable either by premedication, management of drug dosing or lengthening infusion which may promote desensitization.
Adverse effects associated with carboplatin, as monotherapy, clinically observed >10% of the time include:9
Endocrine and metabolic effects (hyponatremia, hypomagnesemia, hypokalemia, hypocalcemia)
Gastrointestinal effects (vomiting, abdominal pain, nausea)
Hematologic and oncologic (bone marrow depression, anemia, leukopenia, neutropenia, thrombocytopenia)
Hepatic (elevated serum alkaline phosphatase)9
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