F. Elferink

Pharmacokinetics of carboplatin after intraperitoneal administration

SummaryThe phamacokinetics of carboplatin, ultrafilterable platinum, and total platinum after intraperitoneal (i. p.) administration were studied in peritoneal fluid, plasma, red blood cells (RBCs), and urine during a phase-I trial in patients with minimal, residual ovarian cancer. Samples were collected from 7 patients who had recived carboplatin (200–500 mg/m2) in 21 dialysis fluid. The fluid was withdrawn after a 4-h dwell. Platinum concentrations were measured by flameless atomic absorption spectrometry, and intact carboplatin was determined by HPLC with electrochemical detection. Peak concentrations of carboplatin in plasma were obtained 2 h after the end of instillation. The mean ratio of peak concentrations of carboplatin in instilled fluid and plasma was 24±11. The peritoneal clearance of carboplatin was 8±3 ml/min, which was 12 times less than the plasma clearance (93±32 ml/min). Due to this clearance ratio, the AUCs for the peritoneal cavity were about 10 times higher than those for plasma. On average, 34%±14% of the dose was still present in the instillation fluid that had been withdrawn after a dwell time of 4 h. In plasma, the mean value of AUC/Dnet (Dnet=Dose — amount recovered from the peritoneal cavity) after i.p. administration was comparable with that of AUC/D after i.v. administration. This means that unrecovered carboplatin (66%) was completely absorbed from the peritoneal cavity. It may be expected from this bioavailability that the maximum tolerated dose (MTD) of i.p.-administered carboplatin with a 4-h dwell is around 1.5 times higher than that after i.v. administration. Overall pharmacokinetic parameters of carboplatin and platinum in plasma were comparable after i.p. and i.v. administration.

Analysis of antitumour [1,1-bis(aminomethyl)cyclohexane]platinum(II) complexes derived from spiroplatin by high-performance liquid chromatography with differential pulse amperometric detection

A reversed-phase high-performance liquid chromatographic analysis was developed for aqua[1,1-bis(aminomethyl)cyclohexane]sulphatoplatinum(II) (spiroplatin) and its hydrolysis and oligomerization products. The platinum complexes were detected by differential pulse amperometry at a hanging mercury drop electrode, at -540 mV vs. Ag/AgCl. The limit of detection was 0.05 microM. Aqueous solutions of spiroplatin appeared to contain the diaqua, monoaquamonosulphato, monoaquamonochloro, dichloro and hydroxo-bridged dimer complexes of [1,1-bis(aminomethyl)cyclohexane]platinum(II) in mutual equilibrium. The equilibrium shifts after dilution in infusion fluids were studied. Detection of these platinum(II) complexes in untreated human plasma ultrafiltrate and urine demonstrated the selectivity of the described analysis.

Secondary screening of platinum compounds in human ovarian cancer xenografts in nude mice

Five TNO platinum compounds were evaluated for antitumor activities in two human ovarian carcinoma tumor lines grown in nude mice. The most active drug, TNO-38, was investigated in five additional lines with a known range of sensitivity to cisplatin. None of the new compounds showed superior activity to cisplatin. The slightly lower activity of TNO-38 as compared to the parent compound was reproducible in all tumor lines. Besides the similarity in the antitumor activity, a remarkable correspondence in platinum distribution and retention at 24 hr of TNO-38 and cisplatin could be observed. Chromatographic analysis of the compounds in their injection fluids showed single peaks for TNO-26 and TNO-38. The degradation products of the latter drugs may have affected their activity and toxicity. These human ovarian cancer xenografts may offer a reliable screening model for selection of a cisplatin analog with a higher therapeutic index or without cross-resistance for treatment in ovarian cancer.

Influence of hydrolysis products of aqua(1,1-bis(aminomethyl)cyclohexane)sulfatoplatinum(II) on toxicity in rats

Aqueous solutions of the cisplatin analog aqua(1,1-bis(aminomethyl)-cyclohexane)sulfatoplatinum(II) (TNO-6, spiroplatin) principally contain hydrolyzed and oligomerized molecules. Sodium sulfate reduces the hydrolysis of the sulfato ligand. We investigated the influence of the equilibrium state on nephrotoxicity of spiroplatin in rats receiving 3 doses of 3 mg/kg with an interval of 8 days. Rats (n = 6) treated with spiroplatin solubilized in isoosmotic sodium sulfate (impaired hydrolysis) showed less toxicity as measured by proteinuria, platinum excretion and body weight, than the group treated with spiroplatin solubilized in 5% glucose. This result indicates that the presence of hydrolysis products plays a role in the toxicity of spiroplatin.

Determination of ethylenediamineplatinum (II) malonate in infusion fluids, human plasma and urine by high performance liquid chromatography

A selective and convenient high-performance liquid chromatographic assay was developed for ethylenediamineplatinum(II) malonate (JM-40) in plasma ultrafiltrate and urine. A mu Porasil silica column (30 cm) was used with acetonitrile-water (90:10, v/v) as the mobile phase and the elution of compounds was monitored by ultraviolet absorbance at 214 nm. A linear dynamic range of at least three decades (1-1000 micrograms/ml) was achieved. The detection limit in plasma ultrafiltrate was 0.35 micrograms/ml. The stability of JM-40 was determined in 0.9% sodium chloride, 5% glucose, plasma ultrafiltrate and urine. More stable drug solutions were obtained with 5% glucose than with 0.9% sodium chloride. JM-40 was also determined in plasma ultrafiltrate and urine samples of one patient receiving short-term infusions of the drug. In plasma ultrafiltrate unmetabolized JM-40 was detected during the first 5 h after administration and had a half-life of 21.3 +/- 1.6 min. The parent drug was excreted in the urine in rapidly decreasing amounts. Eighteen per cent of the dose was recovered as unmetabolized drug during the first 6 h.

Electrochemistry of platinum complexes. I: Polarographic reduction mechanism with reference to electrochemical detection

Abstract The polarographic behaviour of cis -diamminedichloroplatinum(II) (cisplatin) and eight analogue diammineplatinum complexes was studied. In the potential region 0 to −1 V (vs. Ag/AgCl), an adsorption facilitated current was observed for cisplatin which decreased after the potential of zero charge due to decreased adsorption. Adsorption of cisplatin obeyed a linear adsorption isotherm. After the minimum at −1 V, a second, irreversible wave reached a diffusion-controlled plateau at −1.6 V. The reduction of trans -diamminedichloroplatinum(II), (1,1-bis(aminomethyl)cyclohexane)dichloroplatinum(II) (= TNO-1) and the hydrolysed derivatives of cisplatin and TNO-1 reached the plateau value of the diffusion-limited current between 0 and −1 V. At potentials negative to about −1.5 V, catalytic H + -reduction currents were observed for all complexes except cis -dichloro- trans -dihydroxo- cis -bis(isopropylamine)platinum(IV) (= iproplatin, the only platinum(IV) complex investigated). In 0.1 M ammonium chloride solutions, these catalytic currents were increased and appeared at less negative potentials for all the platinum complexes, including iproplatin. A linear calibration plot was obtained for cisplatin up to 1.4×10 −4 M . It is anticipated that differential pulse polarographic detection in HPLC effluents containing ammonium ions will provide a sensitive analytical method for a large range of ammineplatinum complexes, including their metabolites.

Pharmacokinetics of free and total platinum species after rapid and prolonged infusions of aqua(1,1-bis(aminomethyl)cyclohexane) sulfatoplatinum (II) (spiroplatin) during a phase I trial

The pharmacokinetics of the second generation platinum complex aqua(1,1-bis-(aminomethyl)cyclohexane)sulphatoplatinum(II) (spiroplatin, TNO-6) were studied during a phase I evaluation. Thirty patients received 49 cycles of spiroplatin by short term (less than or equal to 10-min), 1-, 3- or 6-h infusion. Dosages given ranged from 5 to 40 mg/m2. Platinum determinations were performed by atomic absorption spectrometry. Up to 5 days after administration platinum concentrations in plasma decayed triexponentially. Pharmacokinetic parameters of total platinum in plasma after short-term and prolonged infusion were similar in terms of terminal half-life (3.7 +/- 1.1 and 3.6 +/- 0.5 days), AUC/dose (548 +/- 106 and 616 +/- 278 min.m2/l), volume of distribution (20 +/- 6 and 27 +/- 81) and total body clearance (2.9 +/- 1.0 and 3.4 +/- 1.8 ml/min), whereas peak plasma concentrations were two times lower after prolonged infusion. The cumulative urinary platinum excretion after short-term infusion was 20 +/- 6%, 30 +/- 6% and 47 +/- 7% of the administered dose after 6, 24 and 120 h, respectively. These values are comparable to those after administration of cisplatin. The half-life of ultrafilterable platinum was 4.4 +/- 0.7 min. The curves of free and total platinum diverged rapidly, reflecting the high reactivity of spiroplatin towards plasma proteins. This high reactivity, most likely caused by the abundant presence of aquated compounds in the injection fluid, may also account for severe and unpredictable nephrotoxicity induced by spiroplatin.