CHAPTER 2: LITERATURE OVERVIEW
2.10 TOXICOKINETICS .1 Absorption
2.10.2 Distribution
Studies have demonstrated that the route of administration determines the distribution and retention of platinum. In a study including male rats (Charles River CD-1) the whole-body retention of radiolabelled platinum (platinum(IV) chloride; single exposure) has been shown to decrease in the following order: intravenous (highest retention), inhalation and oral (Moore et al., 1975a, 1975b, 1975c). The attainment of maximum platinum levels among different organs/tissues differs over time and the distribution of platinum compounds also changes with dose, with the greatest accumulation shown in the kidneys (Holbrook et al., 1975; Lown et al., 1980; Moore et al., 1975a, 1975b, 1975c; Reichlmayr-Lais et al., 1992).
In vitro studies demonstrated protein binding of ammonium tetrachloroplatinate(II) and potassium tetrachloroplatinate(II) to serum albumin and transferrin (Gauggel et al., 1993; Sykes et al., 1985; Trynda and Kuduk-Jaworska, 1994). In human blood samples most of the platinum was found to be associated with protein and about 65-80% of the platinum was found to be located in the erythrocytes (Vaughan and Florence, 1992). Erythrocytes were also found to contain more platinum than the plasma in a study where platinum(IV) chloride was administrated perorally to Sprague-Dawley female rats (Health Council of the Netherlands, 2008).
2.10.2.1 Intravenous administration
Following intravenous administration of radiolabelled platinum to rats, radioactivity was found in all tissues analysed during the first week, with the largest amount in the kidney and the lowest amount in the brain (Table 8). The high concentration of radioactivity found in the kidney (day 1: 6.65% per gram) shows that once platinum is absorbed most of it accumulates in the kidney after which it is excreted in the urine. The liver, spleen, and adrenal gland also contained higher platinum concentrations than the blood. The low radioactivity levels found in the brain indicated that platinum ions cross the blood-brain barrier only to a limited extent (Moore et al., 1975a, 1975b). Decreased platinum levels were found in tissue where the blood concentration was also declined; therefore a relationship between platinum distribution and blood concentration can be suggested (Moore et al., 1975a, 1975b).
This was confirmed by a study conducted by Lown et al. (1980) where male Swiss mice were given single intragastric doses of platinum(IV) sulphate (144 or 213 mg Pt/kg body weight).
Platinum levels in the blood were several times higher than in the brain. Clearance from the whole body was slower than in the rat studies. This could be due to species-specific differences.
In addition, the mice received much higher doses than the rats. In addition, Lown et al. (1980) noted an increased absorption effect with the higher doses given to the mice. Following ten days of an intravenous injection of 1064 μg potassium tetrachloroplatinate(II) (total platinum:
500 μg/rat) to female Lewis rats, 8% of the total platinum recovered was distributed among the organs (no details presented) (Artelt et al., 1999b)
Table 8. Radioactive 191Pt distribution (counts/g wet weight) in the rat following a single intra- venous dose of platinum(IV) chloride(25 µCi/animal)(Moore et al., 1975a)
Tissue 1 day 2 day 7 day 14 day
%/g counts/g %/g counts/g %/g counts/g %/g counts/g
Blood 0.91 22 147 0.81 19 732 0.52 12 774 0.32 7 921
Heart 0.48 11 819 0.50 12 201 0.36 8 805 0.19 4 593
Lung 0.75 18 432 0.66 16 139 0.46 11 180 0.24 5 770
Liver 1.51 36 848 1.28 31 274 1.05 25 732 0.19 4 733
Kidney 6.65 162 227 6.59 160 656 5.66 138 010 1.24 30 195
Spleen 1.68 41 085 1.89 45 840 2.29 55 764 0.86 20 973
Pancreas 0.91 22 208 0.80 19 487 0.60 14 802 0.16 3 973
Bone 0.53 13 146 0.52 12 800 0.37 8 932 0.22 5 440
Brain 0.05 1 150 0.10 2 485 0.02 595 0.01 265
Fat 0.18 4 487 0.18 4 501 0.13 3 201 0.02 429
Testes 0.17 4 186 0.27 6 540 0.16 3 873 0.06 1 431
Adrenal 1.86 45 439 1.74 42 363 1.09 26 667 0.25 6 190
Muscle 0.19 4 798 0.19 4 671 0.14 3 441 0.09 2 146
Duodenal segment
0.52 12 725 0.25 6 044 0.16 4 031 0.06 1 410
2.10.2.2 Inhalation exposure
Moore et al. (1975c) performed a study on male rats (Charles River CD-1) where they were exposed to radiolabelled platinum or platinum oxide via inhalation (7-8 mg/m3; 48 min; particle size not given). It was shown, that the initial lung burdens for radiolabelled platinum metal and platinum oxide represented about 14% and 16% of the initial body burdens. Most of the radioactivity had been eliminated from the gastrointestinal tract within 24 hours, while the lung still contained about 60% of the initial lung burden (Table 6).
In addition to the lungs (day 1: 45462 counts/g) and trachea (day1: 1909 counts/g), the kidneys (day1: 750 counts/g) and bones (day 1: 281 counts/g) were found to contain the highest concentrations of radioactivity when radiolabelled platinum was counted in selected tissues 1-8 days after exposure (Table 9).
The brain contained very small amounts of radiolabelled platinum (1day: 5 counts/g). When exposed by inhalation to 12 mg/m3 of washed Al2O3/Pt (see Section 5.1.2), 5 hours/day, 5 days/week, for three months, only 0.01% of the total platinum was recovered from the organs (liver, spleen, kidneys, adrenals, stomach, femur) with highest amounts in the liver (0.13 μg) and the kidneys (0.042 μg). Following inhalation of 4 mg/m3, only 0.003% was recovered with the highest amount in the kidney (0.016 μg) (Artelt et al., 1999b)
Table 9. Radioactive 191Pt in selected tissues following inhalation exposure to platinum metal (Moore et al., 1975c).
Tissues Days after exposure
1 2 4 8
Blood 61* 43 30 12
Trachea 1909 2510 738 343
Lung 45462 28784 28280 23543
Liver 52 46 37 17
Kidney 750 1002 906 823
Bone 281 258 231 156
Brain 5 3 1 0
Muscle 22 10 28 0
Spleen 39 73 23 5
Heart 37 58 23 5
*mean counts per gram
2.10.2.3 Oral administration
In a long-term study, Bader et al. (1992) and Bogenrieder et al. (1993) (cited in Health Council of the Netherlands, 2008) orally administered platinum salts to male Sprague-Dawley rats, either in their drinking-water or dry feed. Peroral administration to rats has shown, that administration of a water-soluble platinum salts such as platinum(IV) chloride leads to much higher concentrations of platinum in the blood and tissues, than administration of platinum metal (at comparable doses), but the particle size has been found to influence the concentration of platinum metal, especially in the kidneys (IPCS, 1991; Health Council of the Netherlands. 2008).
In these and other animal experiments the absorbed platinum (orally given platinum metal, platinum(II) chloride, platinum(IV) chloride or platinum(IV) sulphate) was distributed to virtually all organs and tissues, with the highest amounts of absorbed platinum found in the kidneys, while low levels have been found in the adipose tissue and brain (Moore et al., 1975a,1975b;
Lown et al., 1980; Reichlmayr-Lais et al., 1992).
2.10.2.4 Subcutaneous administration
In a study conducted by Zhong et al. (1997a, 1975b) it was found that metallothionein synthesis in the liver and kidney were induced when disodium hexachloroplatinate was subcutaneously administratedto rabbits. Hepatic metallothionein contained small amounts of platinum (0.04 g atom/mol protein), whereas renal metallothionein contained higher platinum amounts (2.6 g atom/mol protein). The oxidation state of platinum in metallothionein was found to be +2 and this results suggested that platinum(IV) complexes may be reduced in vivo to platinum(II) compounds that bind to metallothionein. This process may play a significant role in reducing the cytotoxicity of platinum(IV) complexes.
2.10.2.5 Human tissue platinum content
Studies conducted from the early 1965’s (Wester, 1965) have examined the platinum levels in human tissue from humans not occupationally exposed to platinum compounds. It was found that the platinum levels varied greatly and ranged from 0.005-1170 ng/g wet weight and included tissue from the liver, kidney, spleen, lung, heart, muscle, brain and fat (Duffield et al., 1976; Johnson et al., 1976; Zeisler and Greenberg, 1988; Yoshinaga et al., 1990). Earlier findings were confirmed by Benes et al. (2000) that reported a great variation in the platinum content of human tissues. In 70 autopsied individuals (54 males, 16 females; age: 18-76 years) from the North Bohemia territory of the Czech Republic, the platinum content in liver, kidney, and bone was found to be in the range of 2-3920 μg/kg (median: 2 μg/kg), 2.5-750 μg/kg (median: 2.5 μg/kg), and 10-230 μg/kg (median: 10 μg/kg) wet weight, respectively. No significant differences were seen between males and females.
2.10.2.6 Foetal uptake and distribution
Foetal uptake of platinum compounds has been investigated in a few studies and was reported to be very low. In one study (Moore et al., 1975a) pregnant rats where given 25 μCi radiolabelled platinum(IV) chloride intravenously and very low levels of the platinum were present (after 24 hours) in all the foetuses measured, with 0.01% of the dose/g in whole foetal tissue, 0.05% of the dose/g in foetal liver and 0.9% of the dose/g in placental tissue (Lindell, 1997).
In another study in rats, platinum(IV) chloride or platinum metal was administered from four weeks before pregnancy to the twentieth day of gestation (Kirchgessner et al., 1992,1993; cited in Lindell,1997). The platinum was given in the diet in five different concentrations up to 100 mg/kg diet. Platinum levels found in the uterus and in the foeto-placental unit generally was much higher in the platinum(IV) chloride groups compared to the corresponding PGMs, but still represented a very small part of the ingested amount of platinum. The highest platinum levels in the foeto-placental unit were found in the amnion, where about 80-90% of the measured platinum was situated. Platinum concentrations were lowest in the foetuses from the groups given 50 mg/kg and 100 mg/kg platinum(IV) chloride. When platinum(IV) chloride or platinum(II) chloride was given to lactating rats in concentrations of 50 mg/kg and 100 mg/kg diet only platinum(IV) chloride was detected in the milk, while platinum(IV) chloride as well as platinum(II) chloride (at 50 mg/kg and 100 mg/kg levels) were found in the carcass of the offspring after administration. The platinum levels in the offspring was found to be highest at the end of the lactation period and generally higher in the offspring after administration of platinum(IV) chloride
2.10.3 Elimination