Occupational exposure to platinum drugs during intraperitoneal chemotherapy. Biomonitoring and surface contamination.

BACKGROUND: Hyperthermic intraperitoneal chemotherapy (HIPEC) has been introduced over the last decade for the treatment of peritoneal carcinomatosis. In this procedure, heated cytotoxic drugs are administered directly into the abdominal cavity, ensuring cancer cells to be exposed while reducing systemic toxicity. More recently, pressurized intraperitoneal aerosol chemotherapy (PIPAC), where the chemotherapeutic drug is injected into the peritoneal cavity as an aerosol under pressure, has been proposed to patients in palliative situation, as a new approach. The amount of drug used is up to 10 fold lower than in HIPEC. The use of cytotoxic drugs poses an occupational risk for the operating room personnel. This study investigated the potential exposure of the medical staff by biomonitoring and surface contamination measurements, during a HIPEC procedure and a PIPAC procedure. METHOD: Wipe samples were collected from various locations in operating rooms including gloves, hands, devices and floor. Urines samples were collected from 10 volunteers of the medical staff and from a control group. The platinum analysis was performed by inductively coupled plasma mass spectrometry. RESULTS: Significant contaminations were observed on the floor, gloves, shoes and devices. However, urinary platinum was below the limit of quantification (<10 ng/L) for more than 50% of samples from the healthcare workers performing HIPEC and PIPAC. Concentrations did not differ significantly from those reported for the control group. CONCLUSION: There appears to be little risk of exposure to platinum drugs during HIPEC and PIPAC providing the adequate safety measures are implemented.

A validated inductively coupled plasma mass spectrometry (ICP-MS) method for the quantification of total platinum content in plasma, plasma ultrafiltrate, urine and peritoneal fluid.

Oxaliplatin is a platinum (Pt)1 containing antineoplastic agent that is applied in current clinical practice for the treatment of colon and appendiceal neoplasms. A fully validated, highly sensitive, high throughput inductively coupled plasma mass spectrometry (ICP-MS) method is provided to quantify the total Pt content in plasma, plasma ultrafiltrate, urine and peritoneal fluid. In this ICP-MS approach, the only step of sample preparation is a 1000-fold dilution in 0.5% nitric acid, allowing the analysis of 17 samples per hour. Detection of Pt was achieved over a linear range of 0.01-100 ng/mL. The limit of quantification was 18.0 ng/mL Pt in plasma, 8.0 ng/mL in ultrafiltrate and 6.1 ng/mL in urine and peritoneal fluid. The ICP-MS method was further validated for inter-and intraday precision and accuracy (≤15%), recovery, robustness and stability. Short-term storage of the biofluids, for 14 days, can be performed at -4 °C, -24 °C and -80 °C. As to long-term stability, up to 5 months, storage at -80 °C is encouraged. Furthermore, a timeline assessing the total and unbound Pt fraction in plasma and ultrafiltrate over a period of 45 h is provided. Following an incubation period of 5 h at 37 °C, 19-21% of Pt was recovered in the ultrafiltrate, emphasizing the extensive and rapid binding of oxaliplatin-derived Pt to plasma proteins. The described method can easily be implemented in a routine setting for pharmacokinetic studies in patients treated with oxaliplatin-based hyperthermic intraperitoneal perioperative chemotherapy.

Anticancer metal drugs and immunogenic cell death.

Conventional chemotherapeutics, but also innovative precision anticancer compounds, are commonly perceived to target primarily the cancer cell compartment. However, recently it was discovered that some of these compounds can also exert immunomodulatory activities which might be exploited to synergistically enhance their anticancer effects. One specific phenomenon of the interplay between chemotherapy and the anticancer immune response is the so-called "immunogenic cell death" (ICD). ICD was discovered based on a vaccination effect exerted by cancer cells dying from pretreatment with certain chemotherapeutics, termed ICD inducers, in syngeneic transplantation mouse models. Interestingly, only a minority of drugs is able to trigger ICD without a clear-cut relation to chemical structures or their primary modes-of-action. Nevertheless, generation of reactive oxygen species (ROS) and induction of endoplasmic reticulum (ER) stress are clearly linked to ICD. With regard to metal drugs, oxaliplatin but not cisplatin is considered a bona fide ICD inducer. Taken into account that several experimental metal compounds are efficient ROS and ER stress mediators, presence of potent ICD inducers within the plethora of novel metal complexes seems feasible and has occasionally been reported. In the light of recent successes in cancer immunotherapy, here we review existing literature regarding anticancer metal drugs and ICD induction. We recommend a more profound investigation of the immunogenic features of experimental anticancer metal drugs.

Evaluation of oxaliplatin exposure of healthcare workers during heated intraperitoneal perioperative chemotherapy (HIPEC).

The aim of this study was to evaluate air and surface contaminations, and internal contamination of healthcare workers during open-abdomen HIPEC using oxaliplatin. Platinum (Pt) was measured in urine of exposed workers and in multiple air and surface samples. Three successive HIPEC procedures were investigated in each of the two hospitals participating in the study. Analysis of air samples did not detect any oxaliplatin contamination. Heavy contamination of the operating table, the floor at the surgeon's feet, and the surgeon's overshoes were observed. Hand contamination was observed in surgeons using double gloves for intra-abdominal chemotherapy administration, but not in those using three sets of gloves. Pt was not detected in urine samples obtained after HIPEC (<5 ng/L). The main risk of HIPEC is related to direct or indirect skin exposure and can be prevented by correct use of adapted protective equipment.

Urinary concentrations of organophosphorus insecticide metabolites in Japanese workers.

A recent development in analytical chemistry has enabled us to monitor systemic organophosphorus insecticide (OP) exposure at individual levels. At present, however, limited data are currently available on urinary OP metabolite levels worldwide. The purpose of this study was to assess urinary dialkylphosphate (DAP) concentrations in Japanese workers. Urine samples were collected in both summer and winter from 339 Japanese adults who worked as food distributors (FDs, n=164), apple farmers (AFs, n=147) and pest control operators (PCOs, n=28). DAPs were measured by gas chromatography-mass spectrometry after derivatization with pentafluorobenzylbromide. Dimethylphosphate (DMP), diethylphosphate (DEP), dimethylthiophosphate (DMTP) and diethylthiophosphate (DETP) were detected in the urine of over 87% of the studied populations in both seasons. The geometric mean values of total DAPs (nmol g(-1) creatinine), DMP, DMTP, DEP and DETP (µg g(-1) creatinine) in summer and winter were 106.7 and 98.3, 7.0 and 3.8, 3.4 and 4.5, 0.8 and 1.5, and 0.3 and 0.2 for the FDs, 440.8 and 197.7, 33.1 and 10.8, 10.1 and 5.8, 4.2 and 4.7 and 1.6 and 0.8 for the AFs, and 473.4 and 284.6, 28.9 and 22.2, 17.6 and 4.6, 3.5 and 4.4, and 0.5 and 0.6 for the PCOs, respectively, thereby revealing significantly higher concentrations in AFs and PCOs groups than in the FDs in both seasons except for winter DMTP. These DAP concentrations were approximately the same or at lower levels compared with those reported in the previous literature. This is one of the first studies to demonstrate urinary DAP concentrations in Japanese adults.

A comparative study of pharmacokinetics, urinary excretion and tissue distribution of platinum in rats following a single-dose oral administration of two platinum(IV) complexes LA-12 (OC-6-43)-bis(acetato)(1-adamantylamine)amminedichloroplatinum(IV) and satraplatin (OC-6-43)-bis(acetato)amminedichloro(cyclohexylamine)platinum(IV).

PURPOSE: This study compared the pharmacokinetics, tissue distribution, and urinary excretion of platinum in rats after single oral doses of LA-12 and satraplatin. METHODS: Both platinum derivatives were administered to male Wistar rats as suspensions in methylcellulose at four equimolar doses within the range of 37.5-300 mg LA-12/kg body weight. Blood sampling was performed until 72 h, and plasma and plasma ultrafiltrate were separated. Moreover, urine was collected until 72 h, and kidney and liver tissue samples were obtained at several times after administration. Platinum was measured by atomic absorption spectrometry. The pharmacokinetics of platinum was analyzed by population modelling and post hoc Bayesian estimation as well as using non-compartmental pharmacokinetic analysis of the mean concentration-time curves. RESULTS: Platinum was detected in all plasma and ultrafiltrate samples 15 min after oral administration of both compounds and peaked between 3-4 h and 1-3 h, respectively. Similar for LA-12 and satraplatin, the C (max) and AUC values of plasma and ultrafiltrate platinum increased less than in proportion to dose. The mean C (max) and AUC values of plasma platinum observed after administration of LA-12 were from 0.84 to 2.5 mg/l and from 20.2 to 75.9 mg h/l. For ultrafiltrate platinum, the corresponding ranges were 0.16-0.78 mg/l and 0.63-1.8 mg h/l, respectively. The AUC of plasma platinum was higher after satraplatin (P < 0.001). However, administration of LA-12 resulted in significantly higher AUC values of ultrafiltrate platinum after the doses of 150 mg and 300 mg/kg (P < 0.01), respectively, and the C (max) values were significantly higher starting from the dose of 75 mg/kg LA-12 and upward (P < 0.01). Cumulative 72-h urinary recovery of platinum dose was below 5% for both compounds, and it decreased with the dose of satraplatin (P < 0.01), while a numerical decrease was observed after administration of LA-12 that did not reach statistical significance (P = 0.41). The renal clearance of free platinum was similar regardless of the dose and compound administered. Platinum concentrations in the liver homogenate exceeded those in the kidney. Distribution of platinum to tissues was higher after LA-12 compared to satraplatin. The difference in kidney platinum increased with dose and was twofold after 350 mg/kg LA-12. Liver platinum was twofold higher after LA-12 across all four doses. CONCLUSIONS: In conclusion, this first comparative pharmacokinetic study with LA-12 and satraplatin shows that characteristics of platinum exposure evaluated in the plasma, plasma ultrafiltrate and kidney and liver tissues increase less than in proportion to dose following a single-dose administration of 37.5-300 mg/kg to Wistar rats. These findings together with the dose-related elevation in the pharmacokinetic characteristics V/F and CL/F of platinum and ultrafiltrate platinum as well as a drop in platinum urinary recovery are consistent with a dose-related decrease in the extent of oral bioavailability most likely due to saturable intestinal absorption.

Ultra-fast HPLC-ICP-MS analysis of oxaliplatin in patient urine.

A novel method for rapid HPLC-ICP-MS analysis of oxaliplatin in human urine was developed implementing a stationary HPLC phase with a particle size of 1.8 microm. The method allowed a cycle time of <1 min at a HPLC flow rate of 0.9 mL min(-1). Procedural limits of detection of 0.05 microg L(-1) oxaliplatin (150 fg on column) were obtained. Analysis of oxaliplatin in patient urine showed that accurate quantification of the intact drug demanded for storage at -80 degrees C and rapid measurement after thawing.

Time course of the change and amelioration of nedaplatin-induced nephrotoxicity in rats.

Nedaplatin (NDP) is a second-generation antineoplastic platinum complex, with reduced nephrotoxicity. Two experiments were conducted to characterize the time course of changes of its nephrotoxicity and to further evaluate whether hydration is useful for amelioration of nephrotoxicity. In the first experiment, 8-week-old male rats treated with 6 or 9 mg kg(-1) NDP at a single intravenous dose were killed 2, 4, 7 and 14 days after dosing. In the second experiment, nonhydrated (Nhyd) or hydrated (Hyd) rats, treated with a single intravenous dose of 20 mg kg(-1) NDP, were killed 7 days after dosing. Besides renal function and histopathological examinations, the urinary excretion of platinum was measured. Histopathologically, NDP-induced nephrotoxicity was initially characterized by single cell and/or focal necrosis in the epithelium of distal tubules and collecting ducts as well as proximal tubules. In the later stage, subsequent cystic dilatation and regeneration occurred in these affected tubules, but incomplete tissue repair was still observed in the kidney 14 days after dosing. However, NDP-induced nephrotoxicity was dramatically reduced by hydration, while it had no clear effects on myelotoxicity. Measurement of urinary platinum excretion revealed that the total amount of platinum excretion was significantly higher in Hyd-NDP rats than that in Nhyd-NDP rats. In terms of urinary concentration, Hyd-NDP rats showed a lower concentration compared with that in Nhyd-NDP rats. The current results suggest that NDP has the potential risk to cause nephrotoxicity at a human therapeutic dose without hydration and that pre- and post-hydration at dosing can ameliorate this nephrotoxicity.

Determination of the platinum drug cis-amminedichloro(2-methylpyridine)platinum(II) in human urine by liquid chromatography-tandem mass spectrometry.

A validated stable isotope dilution liquid chromatography-tandem mass spectrometry assay for the novel platinum drug cis-amminedichloro(2-methylpyridine)platinum(II) (ZD0473) in human urine has been developed. This method uses selected reaction monitoring on the transition of m/z 393 [M+NH(4)](+) to m/z 304 [M+NH(4)-NH(3)-2 x H(35)Cl](+) for ZD0473, and m/z 400 [M+NH(4)](+) to m/z 310 [M+NH(4)-NH(3)-H(35)Cl-(2)H(35)Cl](+) for the internal standard [(2)H(7)]ZD0473. Standard curves were prepared over the range from 0.15 to 50 microg/ml. The lower limit of quantitation was 0.2 microg/ml for 100 microl of urine. This simple, rapid, reliable, and sensitive method of quantitation displayed acceptable accuracy and precision over the 3 days of assay validation. A novel platinum adduct was formed during the storage of ZD0473 in human urine. The adduct did not correspond to any of the typical sulfhydryl adducts that have been identified previously for platinum drugs. Formation of the adduct was prevented by the addition of 50% (w/v) sodium chloride to the urine. The assay can be used to quantify intact ZD0473 in the urine of subjects dosed with this new platinum drug.

Pharmacokinetics, tissue distribution, and metabolism of 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (NSC 707545) in CD2F1 mice and Fischer 344 rats.

PURPOSE: 17-(Dimethylaminoethylamino)-17-demethoxygeldanamycin (17DMAG) is an analogue of the benzoquinone ansamycin compound 17-(allylamino)-17-demethoxygeldanamycin (17AAG), which is currently being evaluated in clinical trials. Studies were performed in mice and rats to: (1) define the plasma pharmacokinetics, tissue distribution, and urinary excretion of 17DMAG after i.v. delivery; (2) define the bioavailability of 17DMAG after i.p. and oral delivery; (3) characterize the biliary excretion of 17DMAG after i.v. delivery to rats; and (4) characterize, if possible, any metabolites of 17DMAG observed in plasma, tissue, urine, or bile. MATERIALS AND METHODS: Studies were performed in female, CD2F1 mice or male Fischer 344 rats. In preliminary toxicity studies and subsequent i.v. pharmacokinetic studies in mice, 17DMAG i.v. bolus doses of 33.3, 50, and 75 mg/kg were used. In bioavailability studies, i.p. and oral 17DMAG doses of 75 mg/kg were used. In preliminary toxicity studies in rats, i.v. bolus doses of 10 and 20 mg/kg were used, and in i.v. pharmacokinetic studies 10 mg/kg was used. Compartmental and noncompartmental analyses were applied to the plasma concentration versus time data. In mice and rats, concentrations of 17DMAG were determined in multiple tissues. Urine was collected from mice and rats treated with each of the i.v. doses of 17DMAG mentioned above, and drug excretion was calculated until 24 h after treatment. Biliary excretion of 17DMAG and metabolites was studied in bile duct-cannulated rats given a 10 mg/kg i.v. bolus dose of 17DMAG. 17DMAG metabolites were identified with LC/MS. RESULTS: A 75 mg/kg dose of 17DMAG caused no changes in appearance, appetite, waste elimination, or survival of treated mice as compared to vehicle-treated controls. Bolus i.v. delivery of 17DMAG at 75 mg/kg produced "peak" plasma 17DMAG concentrations between 18 and 24.2 microg/ml in mice killed at 5 min after injection. Sequential reduction in the 17DMAG dose to 50 and 33.3 mg/kg resulted in "peak" plasma 17DMAG concentrations between 9.4 and 14.4, and 8.4 and 10.5 microg/ml, respectively. Plasma 17DMAG AUC increased from 362 to 674 and 1150 microg/ml x min when the 17DMAG dose increased from 33.3 to 50 and 75 mg/kg, respectively, corresponding to a decrease in 17DMAG CLtb from 92 ml/min per kg to 75 and 65 ml/min per kg. Plasma 17DMAG concentration versus time data were best fit by a two-compartment open linear model. No potential 17DMAG metabolites were observed in plasma. 17DMAG bioavailability was 100% and 50% after i.p. and oral delivery, respectively. In rats, an i.v. bolus dose of 10 mg/kg produced peak plasma 17DMAG concentrations between 0.88 and 1.74 microg/ml. Plasma 17DMAG concentrations had fallen below the lower limit of quantitation by 180 min and were best fit by a one-compartment open linear model. The plasma 17DMAG AUC was 104 microg/ml x min, corresponding to a 17DMAG CLtb of 96 ml/min per kg. 17DMAG distributed rapidly to all mouse and rat tissues except brain and testes. Only mouse liver contained materials consistent with potential metabolites of 17DMAG, but their concentrations were below the limit of quantitation of the HPLC assay used. Within the first 24 h after delivery, urinary excretion of 17DMAG by mice and rats accounted for 10.6-14.8% and 12.5-16%, respectively, of the delivered dose. By 15 min after i.v. delivery of 10 mg/kg of 17DMAG, rat bile contained 11 new materials with absorbance similar to that of 17DMAG. Four of these proposed metabolites had an Mr of 633, indicating addition of an oxygen. Two of these proposed metabolites had an Mr of 603, implying the loss of one methyl group, and one had an Mr of 589, implying the loss of two methyl groups. The remaining four proposed metabolites had an Mr of 566, 571, 629, and 645, respectively. Biliary excretion of 17DMAG and metabolites accounted for 4.7 +/- 1.4% of the delivered dose, with 17DMAG accounting for 50.7 +/- 3.4% of the biliary excretion. CONCLUSIONS: 17DMAG has excellent bioavailability when given i.p. and good bioavailability when given orally. 17DMAG is widely distributed to tissues and is quantitatively metabolized much less than is 17AAG. The pharmacokinetic and metabolite data generated should prove relevant to the design of additional preclinical studies as well as to contemplated clinical trials of 17DMAG and could be useful in their interpretation.

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.

Oxaliplatin pharmacokinetics during a four-hour infusion.

A new platin compound, oxaliplatin, has significant activity in advanced colorectal carcinomas. However, its pharmacokinetics have not been characterized adequately yet. This study extensively analyzes the pharmacokinetics of both ultrafiltrable (free) and protein-bound platin in 13 patients receiving 130 mg/m2 oxaliplatin as a 4-h infusion in combination with 375 mg/m2 5-fluorouracil as a 24-h infusion for advanced colorectal carcinomas. The interpatient variability was very low for all parameters analyzed. The levels of free platin decreased triphasically, with a mean terminal half-life of 27.3+/-10.6 h. The area under the time-concentration curve was 20.17+/-6.97 microg.h/ml and the total and renal clearances amounted to 222+/-65 and 121+/-56 ml/min, respectively. The values for the volume of distribution and for the maximum concentration at the end of infusion were 349+/-132 liters and 1612+/-553 ng/ml, respectively. On the basis of the simulation of the plasma levels and the urinary excretion of platin following the long-term administration of oxaliplatin as a constant-rate and a chronomodulated infusion, additional analyses are warranted to fully characterize the pharmacokinetics of the drug in these settings.

Pharmacokinetics of cis-malonato[(4R,5R)-4,5-bis(aminomethyl)-2-isopropyl-1, 3-dioxolane]platinum(II) in rats.

The blood concentration-time profile, distribution, and excretion of cis-malonato[(4R,5R)-4,5-bis(aminomethyl)-2-isopropyl-1, 3-dioxolane]platinum(II) (CAS 146665-77-2, SKI 2053R), a new potential anticancer agent, were investigated in rats after intravenous administration of 14C-SKI 2053R. After a single intravenous administration, the radioactivity of blood declined in a biexponential fashion with the initial half-lives of 0.42 h and 0.37 h and with the terminal half-lives of 68.67 h and 64.67 h in male and female rats, respectively. Radioactivity was distributed very rapidly and extensively into all tissues except the central nervous system. The major amount of the radioactivity was found in the gastrointestinal contents, urine, and organs of elimination at all time points. The distribution pattern of 14C-SKI 2053R observed by the measurement of tissue concentrations was in accordance with that observed by whole-body autoradiography. The 0-7 days cumulative urinary and fecal recoveries of total radioactivity after a single dose were 83.0 +/- 4.5 (mean +/- S.D.) and 11.3 +/- 1.0% in male rats and 85.1 +/- 2.6 and 11.3 +/- 2.3% in female rats, respectively, resulting in total recoveries of 94.3 +/- 3.6% in male rats and 96.3 +/- 1.1% in female rats. The 0-24 h cumulative excretions of total radioactivity in the bile after a single dose were 8.7 +/- 0.4 and 15.8 +/- 3.5% in male and female rats, respectively, showing a significant sex difference.

A sensitive postcolumn derivatization/UV detection system for HPLC determination of antitumor divalent and quadrivalent platinum complexes.

A sensitive postcolumn derivatization/UV detection system has been developed for HPLC analysis of antitumor divalent and quadrivalent platinum complexes. It is based on the derivatization of platinum complexes by reaction with sodium bisulfite to corresponding product(s) which has enhanced absorptivity at 280-300 nm. Platinum complexes examined in this study were cisplatin, carboplatin and oxaliplatin (divalent platinum complexes) and oxoplatin and tetraplatin (quadrivalent ones). The proposed detection system was sensitive to all these complexes. Under the detection conditions optimized for individual complexes, the HPLC gave linear relationships between the complex concentration and the peak height. Detection limits at 290 nm with 100 microliters injection were 20 nM for cisplatin, 40 nM for oxoplatin, 60 nM for carboplatin and tetraplatin and 100 nM for oxaliplatin (S/N = 3 at 0.005 AUFS). The proposed system was successfully applied for the determination of cisplatin and oxoplatin in plasma and urine. Pharmacokinetic behavior of oxoplatin and its reduced product cisplatin following a single intravenous injection of oxoplatin in rabbits has been discussed.

Determination of cisplatin and related platinum complexes in plasma ultrafiltrate and urine by high-performance liquid chromatography with on-line radioactivity detection.

A reversed-phase ion-pair chromatographic method with on-line radioactivity detection for the simultaneous determination of 195mPt-labelled cisplatin and related platinum complexes has been developed. With this system a good resolution of various radiolabelled platinum complexes can be achieved. The detection limit of the radioactivity detector is 10 ng of cisplatin (specific activity of 15 MBq/mg cisplatin) per millilitre of urine or plasma ultrafiltrate. The detector response is independent of both the chemical structure of the platinum complexes and the matrix composition of the samples. This method may serve as a reference system for other high-performance liquid chromatographic systems with less specific and sensitive detectors.

Pharmacokinetics of (glycolate-0,0')-diammine platinum (II), a new platinum derivative, in comparison with cisplatin and carboplatin.

The pharmacokinetics of (glycolato-0,0')-diammine platinum (II) (254-S; NSC 375101D), one of the new platinum analogues, was examined in a phase I study of this drug and compared with that of cisplatin and carboplatin. All drugs were given in short-term (30-min) i.v. drip infusions; the doses of 254-S, cisplatin, and carboplatin were 100, 80, and 450 mg/m2, respectively. Platinum concentrations in whole plasma, plasma ultrafiltrate, and urine were determined by atomic absorption spectrometry. After the infusion, the plasma concentration of total platinum for the three agents decayed biphasically. Ultrafilterable platinum in plasma decreased in a biexponential mode after infusions of 254-S and carboplatin, whereas the free platinum of cisplatin showed a monoexponential disappearance. The peak plasma concentrations and AUC for free platinum were 5.31 micrograms/ml and 959 micrograms/min per ml for 254-S, 3.09 micrograms/ml and 208 micrograms/min per ml for cisplatin, and 19.90 micrograms/ml and 3446 micrograms/min per ml for carboplatin, respectively. The mean ratio of plasma ultrafilterable platinum to total platinum were calculated, and the results showed that the protein-binding abilities of 254-S and carboplatin were almost identical. More than 50% of the 254-S was excreted in the urine within the first 480 min after its administration. Thrombocytopenia was reported as a dose-limiting toxicity for both 254-S and carboplatin. This similarity in side effects may mainly be due to the comparable pharmacokinetic behavior of these two platinum compounds.

Excretion kinetics of the DNA adducts of cis-diamminedichloroplatinum(II) formed in vitro in rat urine.

The main adduct of cis-diamminedichloroplatinum(II) (cis-Pt) with DNA, cis-[Pt(NH3)2(dGpdG)], was administered i.p. to rats. Urine was collected daily for 4 days. The adduct was purified by a weak cation exchanger and quantitated by HPLC with UV detection. The recovery of the adduct was 30.0 +/- 7.0% (mean +/- SEM). The main reason for the low recovery was the chemical instability of cis-[Pt(NH3)2 (dGpdG)] in urine as shown in an in vitro incubation. Adjusted for this instability the recovery in urine was greater than 70% of the dose. When cis-Pt-DNA (the molar ratio of cis-Pt to nucleotide = 1:50) was administered i.p. to rats only 1.25 +/- 0.23% of platinum was excreted in urine in the form of cis-[Pt(NH3)2(dGpdG)] and cis-[Pt(NH3)2(dApdG)] during the first 4 days. If the removal of the cis-Pt-DNA adducts from human tissues is to be followed, their possible slow excretion and chemical instability in urine needs to be considered.

The disposition of carboplatin in the beagle dog.

Carboplatin was administered i.v. to four groups of three male beagle dogs at doses of 3, 6, 12, and 24 mg/kg (60-580 mg/m2). Plasma samples were obtained at appropriate times and protein-free plasma ultrafiltrates (PU) were generated with Amicon Centrifree micropartition systems. Urine was collected at 24-h intervals for 96 h. PU and urine samples were analyzed for carboplatin by HPLC and for total platinum by atomic absorption spectrophotometry. Carboplatin accounted for about 90% of the free platinum in plasma. The Cmax and AUCinf values for carboplatin and for free platinum increased linearly with dose. The terminal elimination half-life and mean residence times for carboplatin and free platinum were each about 1 h. Total-body clearances for carboplatin (5.6 l/h per m2) and free platinum (5.1 l/h per m2) were constant over the dose range studied, as were the respective volumes of distribution (5.7 and 5.0 l/m2). A mean of 46% of the dose was excreted as carboplatin in 24-h urine; and by 72 h, 70% of the platinum administered was excreted in the urine. Free platinum was cleared by both renal and non-renal processes. These results show that a dose of carboplatin is rapidly excreted in the urine and that carboplatin and plasma-free platinum exhibit linear pharmacokinetics in the beagle dog.

High-performance liquid chromatographic procedures for the analysis of carboplatin in human plasma and urine.

Specific, sensitive and reproducible high-performance liquid chromatographic procedures were developed for the quantitative analysis of carboplatin in human plasma and urine. Plasma and urine were ultrafiltered with an Amicon Centrifree micropartition system, and samples were injected onto a LiChrosorb diol column. The mobile phase was CH3CN/H2O (92:8, v/v) for plasma and CH3CN/0.015% H3PO4 (89:11, v/v) for urine. The effluents were monitored at 229 nm. Carboplatin eluted by 10 min. The detector response was linear from 0.5 (plasma) or 5 (urine) to 500 micrograms/ml. The lower limit of quantification was 1.0 micrograms/ml plasma and 5.0 micrograms/ml urine. Constituents in plasma and urine, and possible degradation products (cyclobutane mono- and dicarboxylic acids) did not interfere. Within-day precision was less than 4% for plasma and 9% and 4% for urine concentrations of 40 and 401 micrograms/ml, respectively. Within-day accuracy was 96% or greater for both matrices. Carboplatin was not bound to the Centrifree membrane and recovery was 94% for plasma and 96% for urine. The storage stability of carboplatin in water, plasma, plasma ultrafiltrate, and urine and the extent of binding to human plasma proteins were evaluated. The percentage of carboplatin reversibly bound to plasma proteins was minimal (less than or equal to 10%) over a range of 1-50 micrograms/ml. In human plasma at 37 degrees C the drug was stable for about 2 h, but then degraded with a half-life of 32 h. Carboplatin had limited stability in water, plasma, and urine stored at -25 degrees C. Biological samples, therefore, should be stored frozen and analyzed within a week of collection to obtain valid results.