Human pharmacokinetics of carboplatin after oral administration

Hennik, M.B. van; Vijgh, W.J.F. van der; Klein, I.; Vermorken, Jan B.; Pinedo, H.M.

doi:10.1007/bf00273533

Cited by 18 publications

(8 citation statements)

References 3 publications

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“…The biodistribution of ruthenium in the different organs is in line with what has been observed for other ruthenium-containing compounds in mice [32,33], and the elimination half-life predicted on the basis of this study also correlates well with the data formerly reported and points toward a more rapid excretion than that detected for cisplatin [29,30]. Although we are aware of the limitations of such a prediction, overall pharmacokinetics similar to other heavy-metal-containing cytostatic agents can be anticipated, although a more detailed study is highly desirable.…”

Section: Discussionsupporting

confidence: 87%

“…Measurements were done in plasma and selected tissues (tumour, brain, liver, and kidney) by ICP-MS after acidic digestion at m/z 101 from the mice 48 h after the second administration, when we anticipated (from similar studies with other ruthenium-or platinum-based compounds) [29,30] the terminal excretory period with completed distribution (Table 1). High ruthenium concentrations were observed in liver and kidneys, but ruthenium also accumulated at high levels in the tumour.…”

Section: Resultsmentioning

confidence: 99%

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[(p-MeC6H4Pr )2Ru2(SC6H4-p-Bu )3]Cl (diruthenium-1), a dinuclear arene ruthenium compound with very high anticancer activity: An in vitro and in vivo study

Tomšík

Muthná

Řezáčová

et al. 2015

Journal of Organometallic Chemistry

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Section: Discussionsupporting

confidence: 87%

Section: Resultsmentioning

confidence: 99%

[(p-MeC6H4Pr )2Ru2(SC6H4-p-Bu )3]Cl (diruthenium-1), a dinuclear arene ruthenium compound with very high anticancer activity: An in vitro and in vivo study

Tomšík

Muthná

Řezáčová

et al. 2015

Journal of Organometallic Chemistry

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“…[I39] Limitations of oral administration of cisplatin and carboplatin are incomplete absorption, [140] gastrointestinal toxicity [141] and poor antitumour activity,l141] JM216 exhibits no nephrotoxicity, peripheral neurotoxicity or ototoxicity in animals or humans. [142][143][144] The dose-limiting toxicity is myelosuppression, with both thrombocytopenia and leucopenia.…”

Section: Mckeagementioning

confidence: 99%

Comparative Adverse Effect Profiles of Platinum Drugs

1995

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Since the discovery of the biologically active platinum complexes 30 years ago, 2 agents have become widely established in clinical oncology practice. Both cisplatin and carboplatin are platinum(II) complexes with 2 ammonia groups in the cis- position. However, they differ in their solubility, chemical reactivity, dichloride or alicyclic oxygenated leaving groups, pharmacokinetics and toxicology. Cisplatin causes severe renal tubular damage and reduces glomerular filtration, and requires concurrent saline hydration and mannitol diuresis to eliminate potentially lethal and unacceptable damage to the kidneys. Carboplatin, at conventional doses, causes no decrease in glomerular filtration and only minor transient elevations in urinary enzymes. Cisplatin is the most emetic cancer drug in common use, while nausea and vomiting associated with carboplatin are moderately severe. Serotonin release from enterochromaffin gut mucosal cells and stimulation of serotonin 5-HT3-receptors mediates acute emesis. Selective inhibitors of the 5-HT3-receptor protect against cisplatin- and carboplatin-induced nausea and vomiting. Peripheral neurotoxicity is the most dose-limiting problem associated with cisplatin. Loss of vibration sense, paraesthesia and sensory ataxia comes on after several treatment cycles. Carboplatin, however, is relatively free from peripheral neurotoxicity. Audiometry shows cisplatin-induced ototoxicity in 75 to 100% of patients, which may be associated with tinnitus and hearing loss. Ototoxicity is rare with conventional dose carboplatin therapy. Monitoring hearing with audiograms may identify early signs before significant impairment occurs. Cisplatin causes mild haematological toxicity to all 3 blood lineages. Haematological toxicity is dose-limiting for carboplatin, with thrombocytopenia being a greater problem than leucopenia. Although carboplatin is not toxic to the kidney, renal function markedly affects the severity of carboplatin-induced thrombocytopenia. The major clearance mechanism of cisplatin is irreversible binding in plasma and tissues, while carboplatin is cleared by glomerular filtration. Metabolism of cisplatin to aqua, amino acid and protein species is extensive, whereas carboplatin exists mainly as the free unchanged form. Strong relationships between carboplatin renal clearance, glomerular filtration rate, area under the plasma concentration-time curve (AUC) of filterable platinum and severity of thrombocytopenia have prompted dose adjustment according to renal function. New analogues such as JM216 offer the potential advantages of oral administration and few nonhaematological toxicities. Analogues based on the diaminocyclohexane ligand have encountered problematic neurotoxicity.

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“…Studies in mice revealed an oral bioavailability of only 11-15% for carboplatin, with a major proportion of the dose (60-80%) excreted in the faceces. 97 The very low bioavailablity together with the observed gastrointestinal side effects made further oral administration of carboplatin unwarrantable.…”

Section: Orally Active Pt (Iv) Complexesmentioning

confidence: 99%

Platinum‐based anticancer agents: Innovative design strategies and biological perspectives

Au-Yeung

2003

Medicinal Research Reviews

304

185

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The impact of cisplatin on cancer chemotherapy cannot be denied. Over the past 20 years, much effort has been dedicated to discover new platinum-based anticancer agents that are superior to cisplatin or its analogue, carboplatin. Most structural modifications are based on changing one or both of the ligand types coordinated to platinum. Altering the leaving group can influence tissue and intracellular distribution of the drug, whereas the carrier ligand usually determines the structure of adducts formed with DNA. DNA-Pt adducts produced by cisplatin and many of its classical analogues are almost identical, and would explain their similar patterns of tumor sensitivity and susceptibility to resistance. Recently some highly innovative design strategies have emerged, aimed at overcoming platinum resistance and/or to introduce novel mechanisms of antitumor action. Platinum compounds bearing the 1,2-diaminocyclohexane carrier ligand; and those of multinuclear Pt complexes giving rise to radically different DNA-Pt adducts, have resulted in novel anticancer agents capable of circumventing cisplatin resistance. Other strategies have focused on integrating biologically active ligands with platinum moieties intended to selectively localizing the anticancer properties. With the rapid advance in molecular biology, combined with innovation, it is possible new Pt-based anticancer agents will materialize in the near future.

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Human pharmacokinetics of carboplatin after oral administration

Cited by 18 publications

References 3 publications

[(p-MeC6H4Pr )2Ru2(SC6H4-p-Bu )3]Cl (diruthenium-1), a dinuclear arene ruthenium compound with very high anticancer activity: An in vitro and in vivo study

[(p-MeC6H4Pr )2Ru2(SC6H4-p-Bu )3]Cl (diruthenium-1), a dinuclear arene ruthenium compound with very high anticancer activity: An in vitro and in vivo study

Comparative Adverse Effect Profiles of Platinum Drugs

Platinum‐based anticancer agents: Innovative design strategies and biological perspectives

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