E. E. M. Brouwers

The application of inductively coupled plasma mass spectrometry in clinical pharmacological oncology research.

Metal-based anticancer agents are frequently used in the treatment of a wide variety of cancer types. The monitoring of these anticancer agents in biological samples is important to understand their pharmacokinetics, pharmacodynamics, and metabolism. In addition, determination of metals originating from anticancer agents is relevant to assess occupational exposure of health care personnel working with these drugs. The high sensitivity of inductively coupled plasma mass spectrometry (ICP-MS) has resulted in an increased popularity of this technique for the analysis of metal-based anticancer drugs. In addition to the quantitative analysis of the metal of interest in a sample, ICP-MS can be used as an ultrasensitive metal selective detector in combination with speciation techniques such as liquid chromatography. In the current review we provide a systematic survey of publications describing the analysis of platinum- and ruthenium-containing anticancer agents using ICP-MS, focused on the determination of total metal concentrations and on the speciation of metal compounds in biological fluids, DNA- and protein-adducts, and environmental samples. We conclude that ICP-MS is a powerful tool for the quantitative analysis of metal-based anticancer agents from multiple sample sources.

Long-term platinum retention after treatment with cisplatin and oxaliplatin

BackgroundThe aim of this study was to evaluate long-term platinum retention in patients treated with cisplatin and oxaliplatin.Methods45 patients, treated 8–75 months before participating in this study, were included. Platinum levels in plasma and plasma ultrafiltrate (pUF) were determined. In addition, the reactivity of platinum species in pUF was evaluated. Relationships between platinum retention and possible determinants were evaluated.ResultsPlatinum plasma concentrations ranged between 142–2.99 × 103 ng/L. Up to 24% of plasma platinum was recovered in pUF. No platinum-DNA adducts in peripheral blood mononuclear cells (PBMCs) could be detected. Ex vivo incubation of DNA with pUF of patients revealed that up to 10% of the reactivity of platinum species was retained. Protein binding proceeded during sample storage. Sodium thiosulfate (STS) appeared to release platinum from the plasma proteins. Platinum levels were related to time, dose, STS co-administration, and glomerular filtration rates (GFR).ConclusionOur data suggest that plasma platinum levels are related to time, age, dose, GFR, and STS use. Platinum in plasma, probably, represent platinum eliminated from regenerating tissue. Platinum species in pUF were partly present in a reactive form. The effects of the reactivity on long-term consequences of Pt-containing chemotherapy, however, remains to be established.

Persistent neuropathy after treatment with cisplatin and oxaliplatin

Background. The aims of the current explorative study were to assess persistent neuropathy in 45 patients up to 6 years after treatment with cisplatin or oxaliplatin and to determine the most adequate method to evaluate neuropathy. Furthermore, the effect of possible determinants on persistent neuropathy was investigated. Material andmethods. The assessment of neuropathy was performed using a questionnaire, by neurological tests, and by vibration threshold (VT) measurements. Because VT determination gives the most objective information, VT measurements were used for further analyses. Results and discussion. The analyses revealed that neuropathy of the hands was related to follow-up time, with an observed recovery half-life of 6.8 (± 3.1) years. No significant reversibility of neuropathy of the feet within the observation period could be demonstrated. For cisplatin, the severity of neuropathy was related to the cumulative dose and sodium thiosulfate use. Oxaliplatin induced neuropathy did not appear to be related to the dose within the studied dose range. No relationship with platinum levels, renal function, glutathione transferase genotypes, diabetes mellitus, alcohol use, or co-medication could be demonstrated. This study was performed as an explorative study and the issues discussed need to be investigated further.

Ciprofloxacin Strongly Inhibits Clozapine Metabolism : Two Case Reports

We report on two cases of drug-drug interactions between ciprofloxacin and clozapine. The first case was a 46-year-old male patient receiving a daily dose of clozapine 900 mg. He was admitted to hospital with urosepsis and was treated with a 5-day course of ciprofloxacin and amoxicillin. Two days after completion of antibacterial therapy, the patient developed symptoms of rhabdomyolysis. Clozapine therapy was discontinued and measurement of the patient’s clozapine plasma concentration 1 day after cessation of clozapine therapy and 3 days after cessation of ciprofloxacin treatment showed that it was in excess of recommended therapeutic levels. The second patient was a 58-year-old male patient treated with a daily dose of clozapine 300 mg. He was admitted to hospital because of delirium and suspected urinary tract infection or pneumonia. Treatment with ciprofloxacin was initiated. Measurement of clozapine plasma concentrations prior to and 3 days after commencement of ciprofloxacin showed that clozapine concentrations doubled over that time period. We suggest that inhibition of cytochrome P450 (CYP) enzymes 1A2 and 3A4 by ciprofloxacin resulted in delayed clozapine metabolism and elevated clozapine plasma concentrations. This might cause severe adverse effects. We advise using another antibacterial agent or reducing the clozapine dose and monitoring clozapine levels when this antipsychotic agent is used in combination with ciprofloxacin.

The effects of sulfur-containing compounds and gemcitabine on the binding of cisplatin to plasma proteins and DNA determined by inductively coupled plasma mass spectrometry and high performance liquid chromatography-inductively coupled plasma mass spectrometry.

The aim of this study was to investigate the effects of sodium thiosulfate (STS), glutathione (GSH), acetylcysteine (AC), and gemcitabine on the platinum–protein (Pt–protein) and platinum–DNA (Pt–DNA) binding of cisplatin in whole blood. This was done to obtain more insight into the platinum (Pt) binding in whole blood and the effects of modulators on this process. STS, GSH, AC, and gemcitabine were added before and after the incubation of whole blood with cisplatin. Pt levels in plasma and plasma ultrafiltrate and the Pt that is bound to DNA in peripheral blood mononuclear cells were determined using inductively coupled plasma mass spectrometry. Additionally, information on the major Pt–DNA adducts was obtained by separation of the Pt–DNA adducts by high performance liquid chromatography with off-line inductively coupled plasma mass spectrometry detection. Results showed that the reactive Pt levels in whole blood are reduced by STS, GSH, and AC. This reduction was demonstrated by a reduced Pt–protein and Pt–DNA binding in the presence of sulfur compounds. Furthermore, STS and AC seemed to be able to release Pt from proteins. The compounds could hardly release Pt from the DNA. Gemcitabine slightly inhibited Pt–DNA binding and did not alter Pt–protein binding. The type of Pt–DNA adducts found were not altered in the presence of the modulators. In conclusion, the results of this study illustrate that STS, GSH, and AC affect Pt binding in whole blood, which suggests that these compounds could affect Pt binding in patients. By interfering with Pt–DNA and Pt–protein binding, the compounds could influence side effects and cytotoxicity.

Determination of platinum surface contamination in veterinary and human oncology centres using inductively coupled plasma mass spectrometry

The objective of this study was to determine the surface contamination with platinum-containing antineoplastic drugs in veterinary and human oncology centres. Inductively coupled plasma mass spectrometry was used to measure platinum levels in surface samples. In veterinary and human oncology centres, 46.3 and 68.9% of the sampled surfaces demonstrated platinum contamination, respectively. Highest platinum levels were found in the preparation rooms (44.6 pg cm(-2)) in veterinary centres, while maximal levels in human centres were found in oncology patient-only toilets (725 pg cm(-2)). Transference of platinum by workers outside areas where antineoplastic drugs were handled was observed in veterinary and human oncology centres. In conclusion, only low levels of platinum contamination attributable to carboplatin were found in the sampled veterinary oncology centres. However, dispersion of platinum outside areas where antineoplastic drugs were handled was detected in veterinary and human oncology centres. Consequently, not only personnel, but also others may be exposed to platinum.

Inductively coupled plasma mass-spectrometric determination of platinum in excretion products of client-owned pet dogs.

Residues of antineoplastic drugs in canine excretion products may represent exposure risks to veterinary personnel, owners of pet dogs and other animal care-takers. The aim of this study was to measure the extent and duration of platinum (Pt) excretion in pet dogs treated with carboplatin. Samples were collected before and up to 21 days after administration of carboplatin. We used validated, ultra-sensitive, inductively coupled plasma-mass spectrometry assays to measure Pt in canine urine, faeces, saliva, sebum and cerumen. Results showed that urine is the major route of elimination of Pt in dogs. In addition, excretion occurs via faeces and saliva, with the highest amounts eliminated during the first 5 days. The amount of excreted Pt decreased over time but was still quantifiable at 21 days after administration of carboplatin. In conclusion, increased Pt levels were found in all measured excretion products up to 21 days after administration of carboplatin to pet dogs, with urine as the main route of excretion. These findings may be used to further adapt current veterinary guidelines on safe handling of antineoplastic drugs and treated animals.

Determination of platinum originating from carboplatin in canine sebum and cerumen by inductively coupled plasma mass spectrometry

We present highly sensitive, reliable methods for the determination of platinum originating from carboplatin in canine sebum and cerumen. The methods are based on the measurement of platinum by inductively coupled plasma mass spectrometry and allow quantification of 0.15 pg platinum per cm² body surface in canine sebum and of 7.50 pg platinum per sampled ear canal. The sample pretreatment procedure involved extraction of wipe samples followed by dilution with appropriate diluents. The performance of the methods, in terms of accuracy and precision, fulfilled the most recent FDA guidelines for bioanalytical method validation. Validated ranges of quantification were 15.0-1.00 x 10⁴ ng L⁻¹ for platinum in canine sebum extraction solution (corresponding to 15.0 pg per wipe sample or 0.15 pgcm⁻²) and 7.50-1.00 x 10⁴ ng L⁻¹ for platinum in canine cerumen extraction solution (corresponding to 7.50 pg per sampled external acoustic meatus). Canine matrices may not always be obtained in sufficient quantities. Therefore, we also confirmed the legitimacy of the application of human matrix samples for the preparation of calibration standards and quality control samples as alternatives, to be used in future clinical studies. The assays are used to support human biomonitoring studies and pharmacokinetic oncology studies in pet dogs treated with carboplatin.