Assessment of workplace environmental contamination and occupational exposure to cisplatin and doxorubicin aerosols during electrostatic pressurized intraperitoneal aerosol chemotherapy.

BACKGROUND: Electrostatic precipitation pressurized intraperitoneal aerosol chemotherapy (ePIPAC) is a novel approach for intraperitoneal drug delivery. As ePIPAC using cisplatin and doxorubicin is performed in an operating room, the challenge is to safely deliver the chemotherapeutic aerosol intraperitoneally while preventing exposure to healthcare workers. The objective of this study was to describe cisplatin and doxorubicin workplace environmental contamination and healthcare worker exposure during ePIPAC. METHODS: Antineoplastic drugs concentrations of cisplatin and doxorubicin were measured in wipe samples from the operating room, and urine samples were collected from healthcare workers. The air samples were collected in order to detect Cisplatin contamination. Cisplatin was analysed by inductively coupled plasma-mass spectrometry and doxorubicin by ultra-high-performance liquid chromatography coupled with tandem mass spectrometry. RESULTS: No trace of cisplatin was found in the air. Cisplatin and doxorubicin were detected on the operating room floor, surfaces, devices and personal protective equipment even after a cleaning protocol. No traces of cisplatin or doxorubicin were found in the urine samples. CONCLUSION: In this study, no internal contamination was found in the ePIPAC surgical team even after implementing two successive ePIPAC procedures. These results showed the effectiveness of the individual and collective protective measures applied. However, the cleaning procedure during ePIPAC should be respected to limit environmental exposure to chemotherapy to cisplatin and doxorubicin during ePIPAC.

Association of Urine Platinum With Acute Kidney Injury in Children Treated With Cisplatin for Cancer.

Cisplatin is a chemotherapeutic agent highly excreted in urine and known to cause acute kidney injury (AKI). As AKI diagnosis by serum creatinine (SCr) is usually delayed, endeavors for finding early AKI biomarkers continue. This study aims to determine if urine platinum (UP) concentration 24 hours after cisplatin infusion is associated with AKI, and to evaluate the association between urine platinum and tubular damage biomarkers: neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1). Children treated with cisplatin in 12 Canadian centers (April 2013 to December 2017) were included. Urine from the morning after the first cisplatin infusion of the first or second cisplatin cycle was measured for urine platinum, NGAL, and KIM-1. SCr and serum electrolytes were used to detect AKI by either SCr elevation or urinary electrolyte wasting (potassium, magnesium, phosphate). The associations of urine platinum with AKI, NGAL, and KIM-1 were assessed. A total of 115 participants (54% boys, median age, 8.5 years; interquartile range, 4.0-13.4) were included, of which 29 (25%) and 105 (91%) developed AKI defined by SCr and electrolyte criteria, respectively. Higher urine platinum was associated with higher cisplatin dose (Spearman rho, 0.21) and with younger age (Spearman rho, -0.33). Urine platinum was not associated with postinfusion AKIor KIM-1, but was weakly associated with NGAL, particularly in participants without SCr AKI (Pearson's r, 0.22). Urine platinum may be a marker of mild tubular injury but is not likely to be a useful biomarker of clinically evident AKI.

YBX1 mediates autophagy by targeting p110ß and decreasing the sensitivity to cisplatin in NSCLC.

Y-box binding protein 1 (YBX1) is involved in the development of multiple types of tumors. However, the relationship between YBX1 and autophagy in non-small cell lung cancer (NSCLC) remains unclear. In this study, we analyzed the expression and clinical significance of YBX1 and markers of autophagy (LC3I/II) in NSCLC and examined their roles in regulating sensitivity to cisplatin in NSCLC. The retrospective analysis of patients with NSCLC indicated that YBX1 was positively correlated with autophagy. Increased levels of YBX1 or autophagy also observed in NSCLC cells compared with those in 16HBE cells. Compared to the controls, the knockdown of YBX1 expression suppressed autophagy, increased drug sensitivity and promoted apoptosis in response to cisplatin in NSCLC cells by targeting the p110ß promoter and inhibiting p110ß/Vps34/beclin1 signaling pathways. We also demonstrated in an in vivo study that the overexpressed YBX1 effectively increased NSCLC growth and progression and decreased the sensitivity to cisplatin by inducing autophagy in a xenograft tumor model, and these effects were concomitant with the increasing of p110ß and beclin1 expression. Collectively, these results show that YBX1 plays an essential role in autophagy in NSCLC.

A New Sensitive Method for Quantitative Determination of Cisplatin in Biological Samples by Kinetic Spectrophotometry.

This study describes a kinetic spectrophotometric method for accurate, sensitive and rapid determination of cisplatin in biofluids. The developed method is based on the inhibitory effect of cisplatin on the oxidization of Janus Green by bromate in acidic media. The change in absorbance as the criteria of the oxidation reaction was followed spectrophotometrically. To obtain the highest rate of sensitivity, efficient reaction parameters were optimized. Under optimum experimental conditions, a calibration graph was obtained linearly over the range 10.0 - 5750.0 µg L-1 and the limit of detection (3sb/m) was 4.2 µg L-1 of cisplatin. The interfering effect of diverse species was investigated. The developed method was used for the quantification of cisplatin in bio fluids of patients treated with cisplatin, spiked bio fluids and pharmaceutical samples and yielded satisfactory results.

Urinary protein biomarkers of kidney injury in patients receiving cisplatin chemotherapy.

Despite recent progress in the development of novel approaches to treat cancer, traditional antineoplastic drugs, such as cisplatin, remain a mainstay of regimens targeting solid tumors. Use of cisplatin is limited by acute kidney injury, which occurs in approximately 30% of patients. Current clinical measures, such as serum creatinine and estimated glomerular filtration rate, are inadequate in their ability to detect acute kidney injury, particularly when there is only a moderate degree of injury. Thus, there is an urgent need for improved diagnostic biomarkers to predict nephrotoxicity. There is also interest by the U.S. Food and Drug Administration to validate and implement new biomarkers to identify clinical and subclinical acute kidney injury in patients during the drug approval process. This minireview provides an overview of the current literature regarding the utility of urinary proteins (albumin, beta-2-microglobulin, N-acetyl-D-glucosaminidase, kidney injury molecule-1, neutrophil gelatinase-associated lipocalin, and cystatin C) as biomarkers for cisplatin-induced AKI. Many of the well-studied urinary proteins (KIM-1, NGAL, B2M, albumin) as well as emerging biomarkers (calbindin, monocyte chemotactic protein-1, and trefoil factor 3) display distinct patterns of time-dependent excretion after cisplatin administration. Implementation of these biomarker proteins in the oncology clinic has been hampered by a lack of validation studies. To address these issues, large head-to-head studies are needed to fully characterize time-dependent responses and establish accurate cutoff values and ranges, particularly in cancer patients. Impact statement There is growing interest in using urinary protein biomarkers to detect acute kidney injury in oncology patients prescribed the nephrotoxic anticancer drug cisplatin. We aim to synthesize and organize the existing literature on biomarkers examined clinically in patients receiving cisplatin-containing chemotherapy regimens. This minireview highlights several proteins (kidney injury molecule-1, beta-2-microglobulin, neutrophil gelatinase-associated lipocalin, calbindin, monocyte chemotactic protein-1, trefoil factor 3) with the greatest promise for detecting cisplatin-induced acute kidney injury in humans. A comprehensive review of the existing literature may aid in the design of larger studies needed to implement the clinical use of these urinary proteins as biomarkers of kidney injury.

Adverse drug reactions and kinetics of cisplatin excretion in urine of patients undergoing cisplatin chemotherapy and radiotherapy for head and neck cancer: a prospective study.

BACKGROUND: Cisplatin is a high-potency anticancer agent; however, it causes significant adverse drug reactions (ADRs). Potential pharmacokinetic markers must be studied to predict or prevent cisplatin-induced ADRs and achieve better prognosis. This study was designed to investigate the relationship between ADRs and kinetics of cisplatin excretion in the urine of patients undergoing high-dose cisplatin chemotherapy and radiotherapy for head and neck cancer. METHODS: Outpatients with head and neck cancer received a first cycle of high-dose cisplatin chemotherapy (80-100 mg/m2) concurrent to radiotherapy. ADRs (haematological, renal, and gastrointestinal reactions) were classified based on severity by National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE, version 4, grade 0-4). The kinetics of cisplatin excretion in urine was evaluated by high-performance liquid chromatography over three time periods: 0-12, 12-24, and 24-48 h after the administration of cisplatin. Spearman Correlation test and regression analysis were performed to assess the relationship between ADRs and cisplatin excretion in the urine. RESULTS: In total, 59 patients with a mean age of 55.6 ± 9.4 years were analysed; most patients were male (86.4%), white (79.7%), and with pharyngeal tumours in advanced stages (66.1%). The most frequently observed ADRs were anaemia (81.4%), lymphopenia (78%), and nausea (64.4%); mostly grades 1 and 2 of toxicity. The mean cisplatin excretion was 70.3 ± 64.4, 7.3 ± 6.3, and 5 ± 4 µg/mg creatinine at 0-12, 12-24, and 24-48 h, respectively. Statistical analysis showed that the amount of cisplatin excreted did not influence the severity of ADRs. CONCLUSIONS: The most frequent ADRs were anaemia, lymphopenia, and nausea. Grades 1 and 2 were the severities for most ADRs. The period over which the highest cisplatin excretion observed was 0-12 h after chemotherapy, and cisplatin excretion could not predict toxicity.

Development and validation of a LC-MS/MS assay for quantification of cisplatin in rat plasma and urine.

Till date, no analytical method published to detect Cisplatin has been validated according to the U.S. Food and Drug Administration (FDA) guidance using liquid chromatography mass spectrometry (LC-MS/MS). We report, a validated LC-MS/MS method for quantitative determination of cisplatin in rat plasma and urine according to FDA guidlines. Cisplatin is a platinum containing compound used for the treatment of different types of cancers. Quantitative determination of cisplatin has been carried out using atomic absorption spectroscopy, high pressure liquid chromatography with phosphorescence, ultra-violet detection, or with inductively coupled plasma mass spectrometry. Few LC-MS/MS methods have been reported for the analysis of cisplatin either for direct quantification or indirect by derivatizing with organic compounds but none of the reported methods have validated the method. The developed and validated assay presented here is a highly sensitive LC-MS/MS method developed and validated for the quantitative determination of cisplatin following derivatization with diethyldithiocarbamate (DDTC) in order to detect platinum (Pt) of cisplatin, suitable for pharmacokinetic studies in rats and to further use it to study human toxicology. Chromatographic separation was achieved using a Poroshell 120 EC-C18 column (3×50mm, 2.7µm) with a binary gradient mobile phase. Quantification was performed on a triple quadruple with electrospray ionization and detection was performed using multiple reaction monitoring. The method has a limit of detection of 1ng/mL, and the quantifiable range was 3-3000ng/mL in rat plasma and urine. The method was accurate and precise with an accuracy and precision for intra-day and inter-day of ±20% for lower limit of quantitation and of ±15% for low, mid and high quality control samples. This method was successfully applied to study the pharmacokinetic profile of cisplatin in rat plasma and urine given a range of doses from 0.5 to 3.5mg/kg.

A label-free colorimetric aptasensor for simple, sensitive and selective detection of Pt (II) based on platinum (II)-oligonucleotide coordination induced gold nanoparticles aggregation.

Herein, a gold nanoparticles (AuNPs) based label-free colorimetric aptasensor for simple, sensitive and selective detection of Pt (II) was constructed for the first time. Four bases (G-G mismatch) mismatched streptavidin aptamer (MSAA) was used to protect AuNPs from salt-induced aggregation and recognize Pt (II) specifically. Only in the presence of Pt (II), coordination occurs between G-G bases and Pt (II), leading to the activation of streptavidin aptamer. Streptavidin coated magnetic beads (MBs) were used as separation agent to separate Pt (II)-coordinated MSAA. The residual less amount of MSAA could not efficiently protect AuNPs anymore and aggregation of AuNPs will produce a colorimetric product. With the addition of Pt (II), a pale purple-to-blue color variation could be observed by the naked eye. A detection limit of 150nM and a linear range from 0.6µM to 12.5µM for Pt (II) could be achieved without any amplification.

Platinum(II)-Oligonucleotide Coordination Based Aptasensor for Simple and Selective Detection of Platinum Compounds.

Wide use of platinum-based chemotherapeutic regimens for the treatment for carcinoma calls for a simple and selective detection of platinum compound in biological samples. On the basis of the platinum(II)-base pair coordination, a novel type of aptameric platform for platinum detection has been introduced. This chemiluminescence (CL) aptasensor consists of a designed streptavidin (SA) aptamer sequence in which several base pairs were replaced by G-G mismatches. Only in the presence of platinum, coordination occurs between the platinum and G-G base pairs as opposed to the hydrogen-bonded G-C base pairs, which leads to SA aptamer sequence activation, resulting in their binding to SA coated magnetic beads. These Pt-DNA coordination events were monitored by a simple and direct luminol-peroxide CL reaction through horseradish peroxidase (HRP) catalysis with a strong chemiluminescence emission. The validated ranges of quantification were 0.12-240 µM with a limit of detection of 60 nM and selectivity over other metal ions. This assay was also successfully used in urine sample determination. It will be a promising candidate for the detection of platinum in biomedical and environmental samples.

Contamination risk for operators performing semi-closed HIPEC procedure using cisplatin.

AIMS: Aim of this study was to assess operators' safety while performing a semi-closed HIPEC procedure for peritoneal carcinomatosis using cisplatin drugs. METHODS: Environmental air, theater personnel urine, operators' gloves and hand skin contamination were assessed during two non-consecutive working days. Six operating surgeons, two anesthesiologists and two theater nurses were included in the study. Glove samples were collected from the inner surface of the external glove and from the external surface of the inner glove from operating surgeons wearing a double pair of gloves. Personnel urine samples were collected before, after and 24 h from the procedure. RESULTS: Air and urine samples permanently resulted below detectable levels for cisplatin presence on all the tested sources and sessions. Cisplatin contamination was detected on the inner surface of the external gloves and on the outer surface of the inner gloves, but in a lower concentration for the latter. Skin wipe samples were below detectable levels for platinum presence. CONCLUSION: The results suggest that two pairs of gloves are adequate to protect the skin from antiblastic drugs. No sign of direct contact or systemic absorption of drugs was ever detected from the inspected samples. Semi-closed HIPEC technique appears to be a safe procedure for operators.

Production of high specific activity (195m) Pt-cisplatinum at South African Nuclear Energy Corporation for Phase 0 clinical trials in healthy individual subjects.

Platinum agents continue to be the main chemotherapeutic agents used in the first-line and second-line treatments of cancer patients. It is important to fully understand the biological profile of these compounds in order to optimize the dose given to each patient. In a joint project with the Australian Nuclear Science and Technology Organisation and the Nuclear Medicine Department at Steve Biko Academic Hospital, South African Nuclear Energy Corporation synthesized and supplied (195m) Pt-cisplatinum (commonly referred to as cisplatin) for a clinical pilot study on healthy volunteers. Enriched (194) PtCl2 was prepared by digestion of enriched (194) Pt metal (>95%) followed by thermal decomposition over a 3 h period. The (194) PtCl2 was then placed in a quartz ampoule, was irradiated in SAFARI-1 up to 200 h, then decay cooled for a minimum of 34 h prior to synthesis of final product. (195m) Pt(NH3 )2 I2 , formed with the addition of KI and NH4 OH, was converted to the diaqua species [(195m) Pt(NH3 )2 (H2 O)2 ](2+) by reaction with AgNO3 . The conversion to (195m) Pt-cisplatinum was completed by the addition of concentrated HCl. The final product yield was 51.7% ± 5.2% (n = 5). The chemical and radionuclidic purity in each case was >95%. The use of a high flux reactor position affords a higher specific activity product (15.9 ± 2.5 MBq/mg at end of synthesis) than previously found (5 MBq/mg). Volunteers received between 108 and 126 MBq of radioactivity, which is equivalent to 6.8-10.0 mg of carrier cisplatinum. Such high specific activities afforded a significant reduction (~50%) in the chemical dose of a carrier cisplatinum, which represents less than 10% of a typical chemotherapeutic dose given to patients. A good manufacturing practice GMP compliant product was produced and was administered to 10 healthy volunteers as part of an ethically approved Phase 0 clinical trial. The majority of the injected activity 27.5% ± 5.8% was excreted in the urine within 5 h post injection (p.i.). Only 8.5% ± 3.1% of cisplatinum remained in blood pools at 5 h, which gradually cleared over the 6-day monitoring period p.i. At the end of the study (6 days p.i.), a total of 37.4% ± 5.3% of the product had cleared from the blood into urine, and approximately 63% remained in the body. The significantly lower concentration of carrier cisplatinum used for imaging resulted in a well-tolerated product.

Urinary excretion of platinum, arsenic and selenium of cancer patients from the Antofagasta region in Chile treated with platinum-based drugs.

BACKGROUND: Arsenic exposure increases the risk of non-cancerous and cancerous diseases. In the Antofagasta region in Chile, an established relationship exists between arsenic exposure and the risk of cancer of the bladder, lung and skin. Platinum-based drugs are first-line treatments, and many works recognise selenium as a cancer-fighting nutrient. We characterised the short-term urinary excretion amounts of arsenic, selenium and platinum in 24-h urine samples from patients with lung cancer and those with cancer other than lung treated with cisplatin or/and carboplatin. As - Se - Pt inter-element relationships were also investigated. RESULTS: The amounts of platinum excreted in urine were not significantly different between patients with lung cancer and those with other cancers treated with cisplatin, despite the significant variation in platinum amounts supplied from platinum-based drugs. In general, the analytical amounts of excreted selenium were greater than those for arsenic, which could imply that platinum favours the excretion of selenium. For other types of cancers treated with drugs without platinum, excretion of selenium was also greater than that of arsenic, suggesting an antagonist selenium-anti-cancer drug relationship. CONCLUSIONS: Regards the baseline status of patients, the analytical amounts of excreted Se is greater than those for As, particularly, for cisplatin chemotherapy. This finding could imply that for over the As displacement Pt favours the excretion of Se. The analytical amounts of excreted Se were greater than those for As, either with and without Pt-containing drugs, suggesting an antagonist Se-anti-cancer drug relationship. However, it seemed that differences existed between As - Se - Pt inter-element associations in patients treated for lung cancer in comparison with those treated for cancer other than lung. Therefore, knowledge obtained in this work, can contribute to understanding the arsenic cancer mechanism and the As - Se - Pt inter-element association for lung cancer and other types of cancer, which in some cases respond at a linear mathematical model.

Determination of platinum originated from antitumoral drugs in human urine by atomic absorption spectrometric methods.

Cisplatin and carboplatin are the most common platinum-based drugs used in cancer treatment. Pharmacokinetic investigations, the evaluation of the body burden during the treatment, as well as baseline levels of platinum in humans have attracted great interest. Thus, accurate analytical methods for fast and easy Pt monitoring in clinical samples become necessary. In the present study atomic absorption spectrometric methods for the determination of platinum in the forms of cisplatin and carboplatin in human urine were investigated. Platinum, in these different forms, could be determined in urine, after simple sample dilution. Regarding electrothermal atomic absorption spectrometry, the optimum parameters were defined by a central composite design optimization. Multiplicative matrix effects were overcome by using a mixture of HCl and NaCl as modifier. The limit of detection (LOD) was 0.004 mgL(-1) of platinum in the original sample. For the analysis of more concentrated samples, high resolution continuous source flame atomic absorption spectrometry was also investigated. Flame conditions were optimized by a multivariate D-optimal design, using as response the sum of the analyte addition calibration slopes and their standard deviations. Matrix matched external calibration with PtCl(2) calibration solutions, was possible, and the LOD was 0.06 mgL(-1) in the original sample. The results obtained by the proposed procedures were also in good agreement with those obtained by an independent comparative procedure.

Contribution of organic cation transporter 2 (OCT2) to cisplatin-induced nephrotoxicity.

Cisplatin is one of the most widely used anticancer agents for the treatment of solid tumors. The clinical use of cisplatin is associated with dose-limiting nephrotoxicity, which occurs in one-third of patients despite intensive prophylactic measures. Organic cation transporter 2 (OCT2) has been implicated in the cellular uptake of cisplatin, but its role in cisplatin-induced nephrotoxicity remains unknown. In mice, deletion of Oct1 and Oct2 resulted in significantly impaired urinary excretion of cisplatin without an apparent influence on plasma levels. Furthermore, the Oct1/Oct2-deficient mice were protected from severe cisplatin-induced renal tubular damage. Subsequently, we found that a nonsynonymous single-nucleotide polymorphism (SNP) in the OCT2 gene SLC22A2 (rs316019) was associated with reduced cisplatin-induced nephrotoxicity in patients. Collectively, these results indicate the critical importance of OCT2 in the renal handling and related renal toxicity of cisplatin and provide a rationale for the development of new targeted approaches to mitigate this debilitating side effect.

Interaction of Cisplatin with the human organic cation transporter 2.

PURPOSE: Cisplatin is predominantly eliminated in the urine through active secretion. As the solute carrier organic cation transporter 2 (OCT2) is highly expressed in the basolateral membrane of proximal tubules, we determined its contribution to cisplatin transport and assessed the relation of variation in the gene encoding OCT2 (SLC22A2) with the disposition of cisplatin. EXPERIMENTAL DESIGN: Cell lines were transfected using the Flp-In 293 system with the full-length OCT2 cDNA, and platinum concentrations were measured using flameless atomic absorption spectrometry. Pharmacokinetic data were available from 106 cancer patients, and DNA was screened for eight nonsynonymous SLC22A2 variants using direct sequencing. RESULTS: mRNA expression was 36-fold higher and uptake of the model substrate tetraethylammonium was significantly increased (P < 0.0001) in OCT2-transfected cells compared with empty vector-transfected controls. OCT2-mediated transport of cisplatin was saturable, and uptake was increased by approximately 4-fold (P < 0.0001) relative to control cells. Cisplatin inhibited OCT2-mediated transport of tetraethylammonium by up to 97%. The mean +/- SD systemic clearance of unbound cisplatin-derived platinum in the patient population was 29.2 +/- 8.39 L/h, and renal clearance was particularly variable. Only one single nucleotide polymorphism (Ala270Se; rs316019) was identified (minor allele frequency, 7.6%), and it was not found to be associated with any of the studied pharmacokinetic variables (P > 0.05). CONCLUSION: These findings support the hypothesis that OCT2 is a key renal transporter involved in cisplatin elimination. However, known variants in SLC22A2 do not substantially contribute to explaining interindividual pharmacokinetic variability, suggesting that other mechanisms, controlling OCT2 expression, might be involved.

Wipe sampling as a tool for monitoring aerosol deposition in workplaces.

As a complement to traditional exposure assessment, monitoring deposition of aerosols can be a simple and quick screening method for identifying deposited aerosols. In this presentation examples of screening studies, based on wipe sampling in combination with adequate analytical techniques, are described. These screening methods are rapid, simple and easy to carry out. The examples given in this presentation show a broad applicability and the methods are proven useful for assessing aerosol distribution in the workplace as well as to identify target spots for more extensive assessment of a worker's exposure situation.

High performance liquid chromatographic determination of platinum in blood and urine samples of cancer patients after administration of cisplatin drug using solvent extraction and N,N'-bis(salicylidene)-1,2-propanediamine as complexation reagent.

A high performance liquid chromatographic (HPLC) procedure has been developed for the determination of cisplatin, based on the pre-column derivation of platinum(II) with reagent N,N'-bis(salicylidene)-1,2-propanediamine (H2SA2pn). The neutral platinum complex was extracted, concentrated in an organic solvent and then injected (5 microl) on a reverse phase HPLC column, Varian Micro-Pak SP C-18, 5 microm (150 mm x 4.0 mm i.d.). The complex was eluted isocratically using a ternary mixture of methanol/acetonitrile/water (40/30/30, v/v/v) at a flow rate of 1.0 ml/min and was determined by a UV detector set at 254 nm after elution. A detection limit was found to be 4.0 ng per injection. The amounts of platinum in blood serum and urine of cancer patients after administration of cisplatin were observed in a range of 221-298 ng/ml and 43-97 ng/ml with relative standard deviation (R.S.D.) of 3.6-4.6% and 3.5-4.8%, respectively. Preliminary metabolism profiles of Pt concentrations in blood and urine from the patients were established.

Atypical pharmacokinetics and excretion of new platinum analogues in rodents.

PURPOSE: Two new series of platinum complexes with cytotoxic activity in vivo are [Pt(NRCH2)2L2], (R=polyfluorophenyl, L=pyridine or substituted pyridine) and [Pt(NRCH2CH2NR'2)2L(X)], (R, L as before; R'=Me or Et, X=halogen). The aim of this study was to determine the pharmacokinetics and excretion in mice and in isolated perfused rat livers of a representative compound from each class, respectively: Pt103 (R=p-HC6F4, L=pyridine) and Pt109 (R, L as for Pt103, R'=Et, X=I). METHODS: Mice were given intraperitoneal injections of active doses of Pt103, Pt109, or cisplatin in a variety of vehicles. Blood was sampled at several times to 48 h. Some mice were placed in metabolic cages where urine and feces were collected. In isolated, perfused rat livers, perfusate and bile were collected following a dose of Pt103, cisplatin or carboplatin. Platinum was measured in blood, urine, feces, or perfusate by atomic absorption spectroscopy. Three vehicles used were peanut oil, dimethyl sulphoxide, and saline/Tween 20. RESULTS: In contrast to renal excretion of over 70% for cisplatin in saline, urinary excretion of platinum was less than 24% of a dose of Pt109 in peanut oil, less than 21% of P103 in DMSO, and only 4% for Pt103 in peanut oil. Over 60% of Pt103 was eliminated in mouse feces, and 57% was excreted in bile from rat liver. Plasma protein binding of Pt109 was greater than 90% at 6 h following administration in mice. CONCLUSION: In contrast to cisplatin and carboplatin, representatives of two new classes of platinum anticancer agents undergo minimal renal elimination, but are excreted mainly in the bile and feces. If a platinum complex with a similar excretion profile was introduced into the clinic, there might be a therapeutic advantage in terms of drug toxicity and combination therapy with other cytotoxics.

Platinum pharmacokinetics in sulphur-crested cockatoos (Cacatua galerita) following single-dose cisplatin infusion.

OBJECTIVE: To determine the pharmacokinetics of platinum (Pt) in cockatoos. DESIGN: A pharmacokinetic study of Pt, following a single i.v. infusion of cisplatin, was done in six healthy sulphur-crested cockatoos (Cacatua galerita). PROCEDURE: Birds were hydrated for 1 h before and 2 h after a 1-h cisplatin infusion (1 mg/kg, i.v.). Serial blood samples were collected for 96 h after initiation of the infusion and urine was collected for 2 h during the hydration period after cisplatin administration. Tissue samples from 10 organs were obtained at necropsy, 96 h after cisplatin infusion. Total Pt and filterable Pt in plasma, urinary Pt and tissue Pt concentrations were assayed by inductively coupled plasma-mass spectrometry. A noncompartmental pharmacokinetic analysis was performed on the plasma and urine data. RESULTS: For total Pt and filterable Pt, the respective mean systemic clearances were 0.373 and 0.699 L/kg hourly, the steady state volumes of distribution were 4.19 and 0.356 L/kg, and the mean residence times were 111 and 0.512 h. Total plasma Pt displayed a bi-exponential decay profile with average half-lives of 0.398 and 79.0 h, while filterable Pt had a monoexponential decay with mean half-life of 0.413 h. The renal clearance during the 2-h postinfusion period was 0.167 L/kg hourly. The kidneys had the highest Pt accumulation (4.54 micrograms/g DM). CONCLUSIONS AND CLINICAL RELEVANCE: Cisplatin infusion in cockatoos was well tolerated and Pt plasma concentrations were similar to those measured during treatment of solid tumours in human patients. Despite anatomical, physiological and biochemical differences among animal species, the pharmacokinetic disposition of Pt in the cockatoo shares some features with the kinetics reported previously in rodents, dogs and human beings.

Role of NK1 receptors on cisplatin-induced nephrotoxicity in the rat.

The role of NK1 receptors on the nephrotoxicity associated with cisplatin treatment was evaluated. Adult Sprague-Dawley male rats (300-400 g) were treated with saline (0.1 ml/100 g, i.p., every 8 h for 72 h) or the selective NK1 receptor antagonist (GR205171; 2 mg/kg, i.p., every 8 h for 72 h). Treatments were started 5 min before cisplatin (7.5 mg/kg, i.p., single dose). All evaluations were made from 72 h to 96 h after cisplatin. An oral load of 10 ml/kg of water was given at time 0 (72 h after cisplatin). Cisplatin reduced the urinary volume (-45%), creatinine clearance (>90%), lithium clearance (-76%) and urinary potassium excretion (-54%). Protein and sodium excretion was not affected by cisplatin. GR205171 prevented the reduction in urine volume induced by cisplatin. In addition, the decreases in creatinine and lithium clearances induced by cisplatin were also attenuated by the NK1 receptor antagonist. The clearance of creatinine averaged 0.57+/-0.2 ml/min in controls, 0.004+/-0.01 ml/min after cisplatin, and 0.09+/-0.02 ml/min after cisplatin + GR205171. The lithium clearance was 0.09+/-0.04 ml/min in controls, 0.02+/-0.01 ml/min after cisplatin and 0.06+/-0.01 ml/min after cisplatin + GR205171. Cisplatin induced marked necrosis, vacuolation and edema of proximal renal tubules; these changes were considerably reduced in GR205171-treated animals. These results indicate that treatment with a selective NK1 receptor antagonist ameliorated cisplatin-induced renal toxicity in rats, as evidenced by improvements in renal function and histology.