measure total platinum, protein-bound platinum and free- circulating ... MERCK Suprapur nitric acid was used. The stock ... 1:lO) on (a) day 15 (43 ng m1-l). (b) day 21 (34 ng .... manual methods in order to determine the best mode of analysis.
Platinum Determination in Plasma and Urine by Flameless Atomic Absorption Spect rophotometry J. P. Cano, 1. Catalint and M. Bues-Charbit INSERM SCN No. 16, Laboratoire de Pharmacocindtique et Toxicocindtique, Faculte d e Pharmacie, 27 I3oulevard Jean Moulin, 13385 Marseille CCdex 5 , France
Kcy words: platinum determination; flameless atomic absorption spectroscopy.
A method is described for the measurement of total platinum in plasma and urine, using flameless atomic absorption spectrophotometry, which is sensitive and reproducible enough to permit pharmacokinetic studies on cis-dichlorodiammineplatinum(1l). The plasma platinum concentrations are determined after ten-fold dilution in 0.5% nitric acid, and urine is analysed after twenty-fold dilution in distilled water. The use of tantalized-treated graphite furnaces prior t o each dosing series allows one to increase the sensitivity and reproducibility of measurements. A comparative study made o n the classic method, which consists of introducing samples manually, and an original automatic one, confirms the latter’s superiority. By taking ten measurements, the reproducibility of the injections is 1.89%for calibration points containing 100 ng ml-’ of platinum and is 2.47% for those containing 35 ng ml-’ of platinum. The reproducibility of the method was determined o n plasma samples to which cis-DPP had been added, using an automatic sample injection system. It varies between 4.73% and 2.93% for platinum concentrations between 0.32 pg ml-’ and 2.61 pg ml-’. This represents the range of t h e concentrations observed in t h e kinetic studies. The absolute detection limit of platinum is 10 ng ml-’.
cis-Dichlorodiarnmineplatinum(1I) is the first coordination complex of platinum clinically used in the treatment of certain cancers.*-’ Nevertheless, this anti-neoplastic drug is not devoid of important undesirable side effects (nephrotoxicity, gastrointestinal toxicity, myelosuppression). Therefore its pharmacokinetic study proves extremely interesting. From the analytical point of view, in order to specify the distribution, retention and elimination of this compound, analysts used various methods. They drew upon radiolabeled pIatinuni,”13 and more rarely upon x-ray fluorescence ~ p e c t r o r n e t r y . ’ ~ . ’Lately, ~ Bannister et a1.” and Borch er af. have resorted to high performance liquid chromatography in order to measure total platinum in urine, after chloroform extraction of the complex formed with natrium diethyldithiocarbamate (sensitivity limit = 25 ng ml-’). I-Iincal et af.I9selectively measured, by HPLC, the other possible forms of &platinum (aquo-hydroxo-chloro specie^)^'-'^ using ion exchange resins. Chang er ~ 1 used this technique to separate cis-DDP from plasma ultrafiltrate, and proceeded to measure it or1 chromatographic effluents by flameless atomic absorption spectrophotometry. By resorting to these methods, Belt et aL25326 could measure total platinum, protein-bound platinum and freecirculating platinum in the plasma. Unquestionably, flameless atomic absorption spectroscopy methods have won the analysts’ preference at the moment, due to the sensitivity fact or. 25-42 Platinum determination may be performed after mineralization of the s a ~ n p I e s . ~ This ~ * ~ ’step may be essential for tissues. However, most authors directly measure this element
Author to whom correspondence should be addressed.
in biological fluids (plasma, urine, CSF, bile) without preliminary destructive treatment of the samples. In order to increase the reproducibility and the detection limit, Bannister er af.29collected the product on paper imptegnated with a cation-exchange resin in order to determine free circulating platinum. Most kinetic studies undertaken were conducted during periods of observation wluch did not exceed a few days. In order to specify this compound’s pharmacokinetics throughout the duration of a therapeutic course (3-4 weeks), we devised a reproducible and sensitive micro-method f o r analysing total platinum both in plasma and urine using flameless atomic absorption spectrophotometry. ~~
After adequate dilutions, t o t a l platinum was analysed directly in plasma and urine by flameless atomic absorption . spectrophotometry. ~ ~ Apparatus Atomic absorption spectrophotometer. This study was performed using a single beam atomic absorption spectrometer (Instrument Laboratory model IL 157) equipped with a flameless atomization furnace (IL model 555) and an automic sampling system (IL Auto-sampler 254). The latter works in a special way. A nebulizer fixed to an injector operated by a programmer permits an aerosol t o be introduced within a graphite tube heated t o about 125 “C during pre-established time intervals. A regular and uniform quantity o f the sample is t h u s obtained. In addition, this apparatus allows large amounts of samples to be introduced,
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J . P. CANO, J. CATALIN AND M. BUESCHARBIT
thereby improving the sensitivity limit (10 ng ml-' of platinum). The absorbance is registered on a Tarkan 600 W recorder.
Spectrophotometric parameters. The light source was a
platinum hollow cathode lamp (Rank Hilger) wavelength: 265.9 nm; band width: 1 nm; equipped with a deuterium background corrector. Tantalum carbidized graphite t ~ b e s . ~ ~The - ~ ' pyrolytic
graphite tube was coated with a tantalum carbide layer. The carbidization was done using the method of Boiteau et ~ 1 for tin and aluminium determination. However, we adapted this technique to the configuration of IL graphite tubes.
De-ionized water was double distilled on a Heraeus Destamat quartz apparatus. MERCK Suprapur nitric acid was used. The stock solution of cis-DDPf (containing 500pg/ml of platinum) was obtained by dissolving about 16 mg of cis-DDP$ in 20 ml of 0.5% nitric acid by ultra-sonication. Intermediate standard solutions of cis-DDP were prepared by diluting the stock solution successively in 0.5% nitric acid. The plasma standard solutions were made by adding increasing volumes of the last standard solution of cis-DDP to ten-fold diluted plasma control (free from platinum) in 0.5%nitric acid so that the final platinum concentration of the dilutions ranged from 9 to 300 ng ml-'. The urinary standard dilutions were prepared in the same way by addition of increasing volumes of the last dilution of cis-DDP to a 20-fold diluted urine (free from platinum) in distilled water (from 100 ng ml-' to 450 ng ml-' of platinum).
Figure 1. Platinum atomization peaks of a patient's plasma (diluted 1 : l O ) on (a) day 15 (43 ng m1-l). (b) day 21 (34 ng m1-l) and (c) day 29 (20 ng ml-') after short-term infusion (pulverization time of the sample: 30 s).
order to increase the intensity of the atomization signal (Fig. 1). Consequently, corresponding calibration points follow the same operating mode. The graphite furnace parameters are quoted in Table 1. ~~
Samples preparation. Blood samples (5-10 ml) were collected in heparinized tubes and quickly centrifuged at 700 x g at 5°C so as to prevent hemolysis and/or possible 'in vitro' redistribution. Urine samples were collected in flasks, their volumes measured and an aliquot was taken. Samples of plasma and urine were kept frozen until they were analysed. The analysis was performed after a ten-fold dilution of plasma in 0.5% nitric acid and a twenty-fold dilution of urine in distilled water. For very high platinum concentrations (greater than 3 gg ml-' for plasma and 8 mg I-' for urine), samples were diluted in order that the final concentration was within the range of the calibration curves.
Choice of acid
Spectrophotometric determination. Each
spectrometric determination was repeated three times successively. The mean of the atomization peak heights allows one to calculate the concentrations of samples in relation to a standard curve obtained under the same conditions. Quantitative analyses were carried out in two ways. Manually: lop1 of the standard solutions or samples to be analysed were introduced into the graphite tube. Automatically: 5 ml of the dilution to be analysed were placed into the tube of the automatic sampler. The spray was introduced into the graphite tube for 15 s. For low concentrations, the pulverization time of the samples was increased to 30 s in
t The reference substance was provided by Roger Bellon Laboratory, France.
$ 1 mg cis-DPP = 0.65 mg of platinum.
34 JOURNAL OF APPLIED TOXICOLOGY,VOL. 2, NO. 1,1982
Different concentrations of hydrochloric and nitric acids were tested with dilute samples of plasmas having identical platinum concentrations. 0.5% Nitric acid enabled us to obtain the best atomization peak. This solution is not corrosive for the automatic sampling system. Moreover, its slight acidity does not induce a protein precipitate in the nebulizer system (aspiration capillary, atomizer and sample jet). Since no significant variations were observed between acid and aqueous dilutions of urine, the latter were stored. Graphite furnaces
Different qualities of graphite tubes (pyrolytic, non-pyrolytic, and pyrolytic tantalum-treated graphites) were tested. The intensity of the atomization signal obtained with pyrolytic graphite tubes was superior to that obtained with non-pyrolytic ones. However, the reproducibility was poor, and for constant concentrations the absorbance rapidly decreased during a long series of analyses as previously described by Pera and Harder.41 With the tantalization of the pyrolytic graphite tube, the best response and good reproducibility were obtained during a series. Standard curves
Figure 2 shows the linearity of the plasma standard curve over a range of concentrations less than those usually 0 Heyden & Son Ltd, 1982
PLATINUM DETERMINATION IN PLASMA AND URINE BY FLAMELESS ATOMIC ABSORPTION
Table I . Graphite furnace program parameters Drying Temperature
Plasma Manual Automatic
Urine Manual Automatic
Reproducibility of the measures. The standard deviation
and the coefficients of variation were calculated after ten consecutive measurements of the same plasma dilution (35 ng ml-' of platinum). This shows the superiority of calibration points at 99.9% according to Student's t-test (Table 2). Reproducibility and sensitivity of the method. By resorting to an automatic sample injection system, the reproducibility of the method was determined on plasma samples to which cis-DDP had been added at concentrations between 0.32 pg ml-' and 2.61pg ml-' (Table 3). Each sample was analysed ten times using the method described. The results obtained, the standard deviation and the coefficients of variation are shown in Table 3. The sensitivity limit in
Purge gas: Argon U
Table 2. Comparative study of the reproducibility of manual and automatic injections Y)
Manual injection (10 pI injected)
35 ng mi-' plasma solution (10 successive measurements)
n = 10
% I 0
V 0.55 106.6
1.65 1.10 213.2 319.8 Concentration
34.5 33 33 31.5 33
Figure 2. Typical calibration curves (least square regression lines): (a) plasma calibration curve ( y = 0 . 6 7 ~+ 0.11; n = 5; r = 0.999); (b) urine calibration curve ( y = 0 . 0 9 ~+ 0.03; n = 4; r = 0.999).
used. This linearity is still observed for platinum concentrations greater than 300 pg 1-' in ten-fold diluted plasma. Figure 2b illustrates the linearity of the urinary standard curve. Advantages of the automatic mode
A comparative study was conducted on automatic and manual methods in order to determine the best mode of analysis. 0 Heyden & Son Ltd, 1982
32 35.5 33 34.5 36
Arithmetic mean = 33.6 Standard deviation = 1.47 Coefficient of variation = 4.37%
Automatic injection Time deposit 30 s
35 ng mi-' plasma solution (10 successive measurements)
n = 10 Arithmetic mean = 37.2 Standard deviation = 0.92 Coefficient of variation = 2.47%
36 38 38 37 36
36 38 38 38 37
Time deoosit 15 s
68 70 69 67 70
100 ng m1-I plasma solution (10 successive measurements)
68 68 68 69 66
a Full scale deflection:
Arithmetic mean = 68.1 Standard deviation = 1.28 Coefficient o f variation = 1.89%
10 m V .
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Table 3. Recovery of platinum in added plasma (automatic method) Theoretical concentration (ccg ml-')
Experimental values (pg ml-')
Mean (pg mi-')
Standard deviation (%)
2.641 2.696 2.506 2.535
2.620 2.694 2.548
2.664 2.765 2.653
2.632 t 0.077
1.206 1.240 1.298 (5) 1.298 (5)
1.315 (5) 1.327 1.223
1.328 1.270 1.270
0.653 0.648 0.693 0.664
0.699 0.653 0.665
0.625 0.591 0.623
0.651 It 0.031
0.316 0.309 0.313 0.322
0.331 0.335 0.335
0.338(5) 0.319 0.307 (5)
0.322 t 0.01 1
15 s. Pulverization time of the sample: 30 s.
a Pulverization time of the sample:
absolute terms is close to 10 ng ml-' of platinum. From the analytical point of view, the automatic mode provides better precision and reproducibility. From a practical point of view, cycles are considerably shorter, consequently more samples can be analysed in the same time interval.
Body orea.l.4mP Sludced course: 5 t h Infusion durotion'20 mi?
Application Figure 3 illustrates the total plasma platinum decrease after the administration of 170 mg of cis-platinum by a shortterm infusion (90min). This method was applied to the pharmacokinetic study of platinum in 14 patients (children and adults) using various administration schedules (bolus, short-term infusion in single dose and in fractionated dose over 5 or 6 days).4648 We thus confirmed that the platinum half-life is higher (1 89-308 h) for the elimination phase than that usually reported in the literature We particularly applied it to platinum urinary excretion because this heavy metal is most likely responsible for the P,12,13,16130,32,39,40
12 24 36 48 60 72 84 96 106 120 132 144 156 168 Time ( h )
Figure 4. Typical plasma and urinary platinum concentration curves of one patient.
Table 4. Comparison of plasma and urinary platinum concentrations with respect to the various administration schedules Maximum plasma platinum concentrations (1.19 m1-l)
Maximum urinary p Ia t i nurn concentrations by fractions of 12 h (mg 1.')
Single Short-term infusion 15-45 min 30-100 mg m-' in chi 1dret-1~~ and adults47 I 2 3
TI me (days)
Figure 3. Time course of plasma platinum concentration of a patient after administration of 170 mg cis-DDP by short-term infusion (90 min).
36 JOURNAL OF APPLIED TOXICOLOGY,VOL. 2, NO. 1,1982
Fractionated dose4' Short-term infusion 30-150 min 1.68-2.23 20 mg m-* day-' over 5 or 6 days in adults ~
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PLATINUM DETERMINATION IN PLASMA AND URINE BY FLAMELESS ATOMIC ABSORPTION
cis-DDP nephrotoxicity. Figure 4 presents the plasma platinum concentration values (curve 1) and the urinary excretion rate (curve 2) for a child. The plasma platinum concentrations are high during the first hour following the beginning of infusion and the urinary concentrations are very high during the same period. The plasma and urinary data in Table 4 confirm that the kidneys are subjected to high concentrations of platinum after administration of a single dose.46 This could account for the nephrotoxicities classically noticed. We have observed that the administration of cis-DDP in a fractionated dose allows one to minimize nephrotoxic effects, while maintaining plasma levels sufficient to ensure anti-neoplastic activity?' The method which has been developed allows, after dilution, direct analysis of total platinum in plasma and urine using flameless atomic absorption spectrometry. Due to the improvements brought about concerning the treatment of graphite tubes and the use of an automatic
sampling system originally operating, the suggested technique is both reproducible and sensitive. It may be applied to large series of samples, with a reproducibility varying between 2.93% and 4.73% for plasma platinum concentrations between 2.610 pg ml-' and 0.326 pg ml-'. These values represent the range of plasma platinum concentrations classically observed in the kinetic studies after administration of cis-DDP for treatments. Its sensitivity allows one to measure the elimination of platinum at least throughout a course (3-4 weeks) and may also permit kinetic studies on platinum during periods of observation longer than those encountered in literature at present.
Acknowledgements This work was supported by DGRST Contract (N" 79-7-06-72).
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40, S. Ostrow, M. Egorin, P. Hanh, A. Leroy, S.Markus, J. Aisner,
P. Chang, R. Foreman, N. Bachur and P. Wiernik, High-dose cis-dichlorodiammineplatinum (cis-DDP) therapy: Pharmacokinetic analysis and toxicity using furosemide ( F ) , VS mannitol (M)diuresis. Proc, 70th Annu. Meet. AACR 20, Abstract 353, 88 (1979). M. F. Pera and H. C. Harder, Analysis for platinum in biological material by flameless atomic absorption spectrometry. Clin. Chem. 23, 1245-1249 (1977). C. J. Williams, K. E. Stevenson and J. M. A. Whitehouse, Pharmacokinetics and toxicity of cis-diamminedichloroplatinum (DDP) given by I V bolus, 24 or 48 hours infusion. Proc. 15th Annu. Meet. ASCO 20, Abstract C 108, 317 (1979). H. L. Boiteau e t C. Mettayer, Microdosage du plomb. du cadmium, du zinc e t de I'etain dans les milieux biologiques par spectromBtrie d'absorption atomique aprhs mineralisation e t extraction. Analusis 6,350-358 (1978). P. Hocquellet e t N. Labeyrie, Etude de I'atomisation thermoBlectrique sur carbure de tantale du silicium, du germanium, de I'etain e t du plomb. Application A la spectromBtrie d'absorption atomique. Analusis 3, 505-512 (1975). V. J. Zatka, Tantalum treated graphite atomizer tubes for atomic absorption spectrometry. Anal. Chem. 6 0 (3), 538 (1978). J. P. Cano, J. Catalin, J. P. Rigault, M. Bues-Charbit, M. Placidi, C. Raybaud and J. L. Bernard, Pharmacokinetic study of cisdichlorodiammine platinum(l1) in children after rapid infusion. Biomedicine 34 (19811, in press. J. P. Cano, J. Catalin, M. Bues-Charbit e t A. Iliadis, Etudes pharmacocinetiques du platine chez des enfants e t des adultes aprbs administration du cis-DDP selon diffbrents protocoles. (IV, perfusion e t doses fractionnkes). Communication to the Forum de Cancdrologie, Paris. 1 June 1981. J. P. Cano, L. Israel, J. Catalin, M. Bues-Charbit, A. lliadis and J. L. Breau, Clinical pharmacokinetics of cis-DDP in patients after 5-6 days fractionated administration by infusion (20 mg/m2/day). Communication to the 12th Int. Congr. Chemother., Florence, 18-24 July 1981.
Received 9 July 1981; accepted 22 October 1981 0 Heyden 81Son Ltd, 1982
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