Cisplatin metabolites in plasma, a study of their pharmacokinetics and importance in the nephrotoxic and antitumour activity of cisplatin

Daley‐Yates, Peter T.; McBrien, D. C. H.

doi:10.1016/0006-2952(84)90610-5

Cited by 175 publications

(72 citation statements)

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“…Cisplatin was administered intravenously in this set of experiments, because previous studies in rodents demonstrate that less than 1% of the platinum in plasma is of the active, parent form 4 hours after administration. 23 This fact also led to the choice of the slightly higher 0.5 mg/kg dose which is still in the nontoxic range and is much less than that used in clinical settings. As with the pretreatment experiments, cisplatin when given at the time of ischemia significantly decreased sALT levels compared to administration of NSS (Fig.…”

Section: Resultsmentioning

confidence: 99%

Cisplatin prevents high mobility group box 1 release and is protective in a murine model of hepatic ischemia/reperfusion injury

et al. 2009

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The nuclear protein high mobility group box 1 (HMGB1) is an important inflammatory mediator involved in the pathogenesis of liver ischemia/reperfusion (I/R) injury. Strategies aimed at preventing its release from stressed or damaged cells may be beneficial in preventing inflammation after I/R. Cisplatin is a member of the platinating chemotherapeutic agents and can induce DNA lesions that are capable of retaining high mobility group proteins inside the nucleus of cells. In vitro studies in primary cultured rat hepatocytes show that nontoxic concentrations of cisplatin can sequester HMGB1 inside the nucleus of hypoxic cells. Similarly, the in vivo administration of nontoxic doses of cisplatin prevents liver damage associated with a well-established murine model of hepatic I/R as measured by lower circulating serum aminotransferase levels, lower hepatic inflammatory cytokine levels including tumor necrosis factor ␣ and interleukin-6, lower inducible NO synthase expression, and fewer I/R-associated histopathologic changes. The mechanism of action in vivo appears to involve the capacity of cisplatin to prevent the I/R-induced release of HMGB1 as well as to alter cell survival and stress signaling in the form of autophagy and mitogen-activated protein kinase activation, respectively. Conclusion: Low, nontoxic doses of cisplatin can sequester HMGB1 inside the nucleus of redox-stressed hepatocytes in vitro and prevent its release in vivo in a murine model of hepatic I/R. Furthermore, cell survival and stress signaling pathways are altered by low-dose cisplatin. Therefore, platinating agents may provide a novel approach to mitigating the deleterious effects of I/R-mediated disease processes. (HEPATOLOGY 2009;50:565-574.)

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Section: Resultsmentioning

confidence: 99%

Cisplatin prevents high mobility group box 1 release and is protective in a murine model of hepatic ischemia/reperfusion injury

et al. 2009

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“…For cisplatin, which is the most chemically reactive platinum analogue, parent drug accounts for <1% of platinum in plasma ultrafiltrate four hours after an i.p. dose in rats (7). Therefore, elemental platinum concentration in plasma ultrafiltrate may not accurately reflect the concentration profile of active parent drug, especially at later time points, and methods to more specifically estimate parent drug concentration are needed.…”

Section: Introductionmentioning

confidence: 99%

Plasma and Cerebrospinal Fluid Pharmacokinetics of Intravenous Oxaliplatin, Cisplatin, and Carboplatin in Nonhuman Primates

Jacobs

Fox

Dennie

et al. 2005

Clinical Cancer Research

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Purpose: Describe and compare the central nervous system pharmacology of the platinum analogues, cisplatin, carboplatin, and oxaliplatin and develop a pharmacokinetic model to distinguish the disposition of active drug from inert platinum species.Experimental Design: Oxaliplatin (7 or 5 mg/kg), cisplatin (2 mg/kg), or carboplatin (10 mg/kg) was given i.v. Serial plasma and cerebrospinal fluid (CSF) samples were collected over 24 hours. Plasma ultrafiltrates were prepared immediately. Platinum concentrations were measured using atomic absorption spectrometry. Areas under the concentration Â Â Â time curve were derived using the linear trapezoidal method. CSF penetration was defined as the CSF AUC 0-24 /plasma ultrafiltrate AUC 0-24 ratio. A four-compartment model with first-order rate constants was fit to the data to distinguish active drug from inactive metabolites.Results: The mean F F SD AUCs in plasma ultrafiltrate for oxaliplatin, cisplatin, and carboplatin were 61 F F 22, 18 F F 6, and 211 F F 64 Mmol/L hour, respectively. The AUCs in CSF were 1.2 F F 0.4 Mmol/L hour for oxaliplatin, 0.56 F F 0.08 Mmol/L hour for cisplatin, and 8 F F 2.2 Mmol/L hour for carboplatin, and CSF penetration was 2.0%, 3.6%, and 3.8%, respectively. For oxaliplatin, cisplatin, and carboplatin, the pharmacokinetic model estimated that active drug accounted for 29%, 79%, and 81% of platinum in plasma ultrafiltrate, respectively, and 25%, 89%, and 56% of platinum in CSF, respectively. The CSF penetration of active drug was 1.6% for oxaliplatin, 3.7% for cisplatin, and 2.6% for carboplatin.Conclusions: The CSF penetration of the platinum analogues is limited. The pharmacokinetic model distinguished between active drug and their inactive (inert) metabolites in plasma and CSF.

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“…However, the renal proximal tubule cells are well-differentiated, non-dividing cells that are not killed by other DNA-damaging agents (6). Early work suggested that a metabolite of cisplatin is responsible for the nephrotoxicity (7). Several steps in the metabolic pathway through which cisplatin is bioactivated to a nephrotoxicant have recently been identified (8)(9)(10)(11)(12)(13).…”

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confidence: 99%

Cisplatin-Induced Toxicity Is Associated with Platinum Deposition in Mouse Kidney Mitochondria in Vivo and with Selective Inactivation of the α-Ketoglutarate Dehydrogenase Complex in LLC-PK₁ Cells

et al. 2006

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The anti-cancer drug cisplatin is nephrotoxic and neurotoxic. Previous data support the hypothesis that cisplatin is bioactivated to a nephrotoxicant. The final step in the proposed bioactivation is the formation of a platinum-cysteine S-conjugate followed by a pyridoxal 5'-phosphate (PLP)-dependent cysteine S-conjugate β-lyase reaction. This reaction would generate pyruvate, ammonium and a highly reactive platinum (Pt)-thiol compound in vivo that would bind to proteins. In the present work, the cellular location and identity of the PLP-dependent cysteine S-conjugate β-lyase was investigated. Pt was shown to bind to proteins in kidneys of cisplatin-treated mice.The concentration of Pt-bound proteins was higher in the mitochondrial fraction than in the cytosolic fraction. Treatment of the mice with aminooxyacetic acid (AOAA, a PLP-enzyme inhibitor), which had previously been shown to block the nephrotoxicity of cisplatin, decreased the binding of Pt to mitochondrial proteins, but had no effect on the amount of Pt bound to proteins in cytAspAT, cytosolic aspartate aminotransferase; DCVC, S-(1,2-dichlorovinyl)-L-cysteine; DMEM, Dulbecco's Modified Eagle's Medium; GFAAS, graphite furnace atomic absorption spectrometry; FBS, fetal bovine serum; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; GDH, glutamate dehydrogenase; GGT, γ-glutamyl transpeptidase; GTK, glutamine transaminase K; HBSS, Hanks' balanced salt solution; KGDHC, α-ketoglutarate dehydrogenase complex; LDH, lactate dehydrogenase; MDH, malate dehydrogenase; mitAspAT, mitochondrial aspartate aminotransferase; MTT, 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide; pmitAspAT, precursor of mitochondrial aspartate aminotransferase; PLP, pyridoxal 5'-phosphate; PMP, pyridoxamine 5'-phosphate; SD, standard deviation; SEM, standard error of the mean; TFEC, S-(1,1,2,2-tetrafluoroethyl)-L-cysteine. NIH Public Access Author ManuscriptBiochemistry. Author manuscript; available in PMC 2014 August 14. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript the cytosolic fraction. These data indicate that a mitochondrial enzyme catalyzes the PLPdependent cysteine S-conjugate β-lyase reaction. PLP-dependent mitochondrial aspartate aminotransferase (mitAspAT) is a mitochondrial enzyme that catalyzes β-elimination reactions with cysteine S-conjugates of halogenated alkenes. We reasoned that the enzyme might also catalyze a β-lyase reaction with the cisplatin-cysteine S-conjugate. In the present study mitAspAT was stably overexpressed in LLC-PK 1 cells. Cisplatin was significantly more toxic in confluent monolayers of LLC-PK 1 cells that overexpressed mitAspAT when compared to control cells containing vector alone. AOAA completely blocked the cisplatin toxicity in confluent mitAspATtransfected cells. The Pt-thiol compound could rapidly bind proteins and inactivate enzymes in close proximity to the PLP-dependent cysteine S-conjugate β-lyase. Treatment with 50-or 100 µM cisplatin for 3 h, followed by removal of cisplatin from the medium ...

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Cisplatin metabolites in plasma, a study of their pharmacokinetics and importance in the nephrotoxic and antitumour activity of cisplatin

Cited by 175 publications

References 10 publications

Cisplatin prevents high mobility group box 1 release and is protective in a murine model of hepatic ischemia/reperfusion injury

Cisplatin prevents high mobility group box 1 release and is protective in a murine model of hepatic ischemia/reperfusion injury

Plasma and Cerebrospinal Fluid Pharmacokinetics of Intravenous Oxaliplatin, Cisplatin, and Carboplatin in Nonhuman Primates

Cisplatin-Induced Toxicity Is Associated with Platinum Deposition in Mouse Kidney Mitochondria in Vivo and with Selective Inactivation of the α-Ketoglutarate Dehydrogenase Complex in LLC-PK₁ Cells

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Cisplatin metabolites in plasma, a study of their pharmacokinetics and importance in the nephrotoxic and antitumour activity of cisplatin

Cited by 175 publications

References 10 publications

Cisplatin prevents high mobility group box 1 release and is protective in a murine model of hepatic ischemia/reperfusion injury

Cisplatin prevents high mobility group box 1 release and is protective in a murine model of hepatic ischemia/reperfusion injury

Plasma and Cerebrospinal Fluid Pharmacokinetics of Intravenous Oxaliplatin, Cisplatin, and Carboplatin in Nonhuman Primates

Cisplatin-Induced Toxicity Is Associated with Platinum Deposition in Mouse Kidney Mitochondria in Vivo and with Selective Inactivation of the α-Ketoglutarate Dehydrogenase Complex in LLC-PK1 Cells

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Cisplatin-Induced Toxicity Is Associated with Platinum Deposition in Mouse Kidney Mitochondria in Vivo and with Selective Inactivation of the α-Ketoglutarate Dehydrogenase Complex in LLC-PK₁ Cells