Pharmacokinetics of intraperitoneal oxaliplatin: experimental studies.

BACKGROUND AND OBJECTIVES: Oxaliplatin is an antineoplastic platinum-based compound which has shown significant activity against advanced colon cancer. For cancers occurring within the abdominal cavity, the advantage of intraperitoneal chemotherapy is the high drug concentration that can be achieved locally with low systemic toxicity. Using a rat model, this study was designed to compare the pharmacokinetics and tissue absorption of intraperitoneal versus intravenous oxaliplatin. METHODS: In the first phase of this study, fifteen Sprague Dawley rats were given a single dose of oxaliplatin then randomized into three groups according to dose and route of delivery (5 mg/kg intravenously, 5 mg/kg intraperitoneally, or 25 mg/kg intraperitoneally). In the second phase, 10 Sprague Dawley rats were given a continuous intraperitoneal perfusion of oxaliplatin (15 mg/kg) and randomized into two groups according to the temperature of the peritoneal perfusate (normothermic vs. hyperthermic). In both phases, peritoneal fluid and blood were sampled using a standardized protocol. At the end of each procedure the animals were sacrificed. Selected tissue samples were taken in the second phase only. For all samples, platinum levels were measured by direct current (d-c) plasma emission spectroscopy. RESULTS: When oxaliplatin was delivered at 5 mg/kg the area under the curve (AUC) of the peritoneal fluid was 15-fold higher with intraperitoneal administration as compared to intravenous administration (P < 0.0001). The AUC ratio (AUC peritoneal fluid/AUC plasma) was 16 (+/- 5):1 for intraperitoneal delivery as opposed to 1:5 (+/- 2) for intravenous delivery (P = 0.0059). The AUC ratio for intraperitoneal oxaliplatin at 25 mg/kg was 17 (+/- 8):1. With the exception of the kidneys and the mesenteric nodes, tissue samples in the hyperthermic group exhibited increased oxaliplatin concentrations. These differences were not significant. For both groups colon tissues had the highest oxaliplatin concentrations. CONCLUSIONS: These experiments demonstrated that the exposure of peritoneal surfaces to oxaliplatin was significantly increased with intraperitoneal administration. Although the differences were not statistically significant, hyperthermia did show a trend toward the enhancement of tissue absorption of oxaliplatin. The high concentration of drug observed in colonic tissues suggests the need for clinical studies to evaluate intraperitoneal oxaliplatin for microscopic residual tumor after surgical resection of colon malignancies.

A pharmacokinetic model and the clinical pharmacology of cis-platinum, 5-fluorouracil and mitomycin-C in isolated pelvic perfusion.

PURPOSE: An isolated pelvic perfusion technique using multiple agents was used both in patients with unresectable recurrent pelvic neoplasms and as a preoperative therapy for advanced pelvic malignancy. METHODS: The technique consisted of vascular occlusion via transfemoral balloon catheters, circulation and drug infusion using standard hemodialysis technology, and a 45-min isolation period. Blood and urine samples were analyzed for the levels of cis-platinum (17 patients, 21 courses of therapy, 50-100 mg/m2, infusion 0-10 min), 5-fluorouracil (12 patients, 14 courses, 1500 mg/m2, infusion 1/3 dose 0-1 min, 2/3 dose 1-20 min) and mitomycin-C (11 patients, 14 courses, 10-20 mg/m2, infusion 10-20 min). An empirical, four-compartment pharmacokinetic model was developed to establish drug distribution curves for the pelvic and systemic circulations and to yield valid estimates of the pharmacokinetic parameters. RESULTS: Pelvic isolation of drug was demonstrated by the pelvic-systemic drug exposure ratios of 6.0:1 for cis-platinum, 8.4:1 for 5-fluorouracil and 9.0:1 for mitomycin-C. Isolation at the L3-4 interspace resulted in minor urine drug elimination during isolation (cis-platinum 7.2% of drug, 5-fluorouracil 2.4% and mitomycin-C 2.5%). Because drug infusion was limited to the first 20 min of isolation, drug levels at the end of the isolation period were reduced to the extent that no extracorporeal drug removal mechanism was needed. CONCLUSION: These pharmacokinetic results indicate that this isolation technique has the potential to provide increased therapeutic indices and is a suitable system for evaluating fast-acting highly toxic experimental drugs to human pelvic cancers which are poorly responsive to conventional clinical protocols.

Preoperative therapy for advanced pelvic malignancy by isolated pelvic perfusion with the balloon-occlusion technique.

BACKGROUND: Although the technique of isolated pelvic perfusion dates back to the time of Creech (1959) and has been used by a variety of authors to treat unresectable neoplasms, the inherent complexity of the open procedure limited its widespread use. We simplified the technique through use of the balloon-occlusion technique for aortic and caval control. Our initial efforts used this technique for unresectable pelvic cancer, but recently we used this as preoperative therapy for advanced pelvic malignancy. METHODS: Isolated pelvic perfusion was accomplished by placement of balloon-occlusion catheters (Fogerty 8) in the aorta and inferior vena cava (IVC) at L3 vertebral body level via the common femoral artery and vein and establishing inflow and outflow catheter connections to a hemodialysis pump that generated a flow rate of 150-300 ml/min. Chemotherapy drugs were infused at times 0, 10, and 20 min. 5-Fluorouracil (5-FU; 1,500 mg/M2), cis-platinum (50-100 mg/M2), and mitomycin (15-20 mg/M2) were given by normothermic perfusion over a 45-min period. Forty isolated perfusions were carried out in 25 patients. Patients were evaluated by clinical examination, biochemical tests, computed tomography (CT) and magnetic resonance imaging (MRI) scans, and surgical exploration. RESULTS: Pelvic perfusion generally achieved pelvic systemic exposure ratios (area under the curve) between 5 and 10:1 for all three drugs: mean ratios were 11.4 (5-FU), 6.0 (cisplatin), and 9.0 (mitomycin). The amount of leaking to the systemic circuit ranged from 28 to 38%. Of 15 patients treated for palliation, there was one objective partial response (PR). Ten patients had symptomatic improvement of pain, two had complete pain relief (CR), and eight had partial pain relief, ranging from 3 weeks to 3 months (median, 5 weeks). Six of 10 patients with adequate carcinoembryonic antigen (CEA) follow-up data had a reduction in CEA levels (mean change, 35 units). Of 10 preoperative patients, there was one CR among five rectal cancer patients; and four of five PRs among patients with other pelvic malignancies: two PRs in patients with epidermoid cancer and one PR each in patients with endometrial cancer and metastatic anorectal melanoma. CONCLUSION: Pelvic perfusion by a simplified balloon-occlusion technique provides palliation for most patients with advanced pelvic malignancy and may increase resectability and improve tumor control in patients amenable to resection.

Intraoperative hyperthermic lavage with cisplatin for peritoneal carcinomatosis and sarcomatosis.

Intraoperative hyperthermic lavage with cisplatin was studied in 8 patients with peritoneal carcinomatosis and sarcomatosis. A dose of 50 mg/m2 of cisplatin used for 2 hours with an intraperitoneal temperature of 41 degrees to 43 degrees C was used. Pharmacokinetic studies showed that cisplatin left the abdomen and pelvis by simple diffusion with a half life of 48 minutes in the peritoneal fluid. Eighty-six percent of the drug was absorbed into the plasma within 2 hours but only 6.9% was excreted into the urine. The area under the curve ratio for peritoneal fluid to plasma was 6.9. The quantity of cisplatin in tissue from the abdomen or pelvis was extremely variable. It was 1.85-10.28 micrograms cisplatin/g tumor and < 0.57-7.90 micrograms/g normal tissue. Comparison of pharmacologic parameters of hyperthermic to normothermic cisplatin administration showed no significant differences.

Isolated pelvic perfusion for unresectable cancer using a balloon occlusion technique.

Previously irradiated recurrent pelvic malignancy is refractory to most treatment modalities. Ten patients with local recurrences (six with rectal cancer; three, anal cancer; and one, anorectal melanoma) were treated with a total of 17 courses of isolated pelvic perfusion chemotherapy (12 with multiple agents) using standard hemodialysis technology. Aortic and inferior vena caval occlusion was maintained via transfemoral balloon catheters, with a single intraoperative balloon disruption. Mean pelvic-systemic drug exposure ratios were 9.8:1 for fluorouracil, 4.8:1 for cisplatin, and 4.4:1 for mitomycin C. Results were three partial responses (two patients subsequently underwent resection) and three minor responses, all in patients with a visible tumor. Pelvic pain was relieved in six of eight symptomatic patients (mean duration, 4 months). Using limited access, this procedure produces high pelvic-systemic concentration gradients, prolonged palliation for recurrent pelvic cancers, and increased resectability in selected patients.

A direct current plasma emission spectrometric procedure for the assay of silicon in urine.

A method for the assay of silicon in urine has been developed using direct current plasma emission spectroscopy. Urine is directly aspirated into the argon plasma, and the silicon emission is measured at 251.6 nm. There is a moderate matrix effect which is not compensated by the addition of lithium chloride as an ionization suppressor. The use of calibration standards in an urine-like matrix gives the best analytical results as documented by serial dilution and standard addition studies. The method is linear over the entire range of urine concentrations normally encountered (0 to 50 mg per L). The lower detection limit is 0.05 mg per L and the coefficients of variation at the 2.7 mg per L and 5.9 mg per L levels are 5.8 percent and 11.5 percent, respectively. Urine from ten randomly chosen volunteers shows a considerable between subject variation in silicon concentration (mean 12.5 +/- 8.3 mg per L, range 1.8 to 51.6 mg per L) which is positively associated with vegetable intake. Urine from 39 hospital patients on a standardized diet shows much less variation in concentration (mean 4.1 +/- 3.2 mg per L, range 0.1 to 18.6 mg per L), indicating that the urine silicon assay is likely to be useful in metabolic studies only if diet is controlled.

Pharmacokinetic and toxicity evaluation of five-day continuous infusion versus intermittent bolus cis-diamminedichloroplatinum(II) in head and neck cancer patients.

We administered cis-diamminedichloroplatinum(II), 30 mg/m2/day for 5 days by continuous infusion to six patients with head and neck cancer, and compared the total and filterable plasma concentrations of platinum, and toxic effects, with those observed in five additional patients who received the same dose and schedule of cis-diamminedichloroplatinum(II) by intermittent bolus. In the continuous infusion group, the total 5-day exposure to filterable platinum, determined from the area under the concentration-time curve, was 1.5 to 2-fold higher (P less than 0.01) than that observed in the intermittent bolus group although the maximum filterable platinum concentration achieved was 8-fold lower (P less than 0.01). These differences were not reflected by total platinum levels. Subclinical nephrotoxicity, as judged by monitoring the urinary excretion of the renal enzymes N-acetyl-beta-D-glucosaminidase and alanine aminopeptidase, as well as ototoxicity, and the incidence and severity of nausea and vomiting were similar in both groups. In contrast, myelosuppression, and hypomagnesemia were more frequent in the continuous-infusion patients, suggesting that the total exposure to free platinum contributes more to these toxicities than peak levels achieved. Considering the clinically acceptable toxicity observed after administration by continuous infusion, we recommend larger therapeutic trials to define the efficacy of increased tumor exposure to filterable platinum.

Continuous-infusion cisplatin and bolus 5-fluorouracil in colorectal carcinoma.

Twenty-one evaluable patients with metastatic colorectal carcinoma were treated with a combination of continuous-infusion cisplatin (25 mg/m2/day X 3 days) and bolus 5-fluorouracil (400 mg/m2/day X 3 days). Toxicity was minimal. Seven patients (33%) responded. All responses were observed among the 16 previously untreated patients (44%) and lasted a median of 30 weeks. The results indicate the need for phase III trials of this treatment.

A phase I trial of continuous infusion cisplatin.

Treatment with continuous infusions of cisplatin results in increased filterable drug exposures as measured by the area under the curve (AUC) of nonprotein-bound plasma platinum levels. To determine the dose-limiting toxicity and optimal method of administration, 24 patients were treated with continuous infusions of cisplatin at a dose rate of 25 mg/M2/day in a limited Phase I trial. A total of 47 courses were given. Nine patients received 13 courses of 4 days duration, 19 received 29 courses of 5 days duration, and five received courses of 6 or 7 days duration. Dose-limiting toxicity was found to be leukopenia: 42% of patients receiving the 5-day treatment developed a nadir count of less than 3000 cells/mm3. Nausea and vomiting were easily controlled. Minimal nephrotoxicity occurred in five patients and was associated with daily volume expansion with 2 l of 0.9% NaCl solution in four patients. All other patients were given 3 l of daily volume expansion during treatment. Responses were seen in 6 of 22 evaluable patients (27%). It is concluded that continuous infusion cisplatin at a dose rate of 25 mg/M2/day can be given safely for 5 days as a single agent if concomitant volume expansion with at least 3 l of 0.9% NaCl solution is given daily. Phase III comparative trials with a conventional bolus and newer high-dose regimens for response and toxicity are indicated.

Cisplatin administered as a continuous 5-day infusion: plasma platinum levels and urine platinum excretion.

Total and filterable platinum in plasma were monitored for seven courses (five patients, 25 mg/m2/day) using continuous 5-day infusions and one 30-minute infusion at a similar dose level (120 mg/m2). Maximum filterable (non-protein-bound) platinum levels (0.1-0.3 mg/L) for the extended infusions were ten to 40 times lower than that for the short-term infusion (4.0 mg/L). Filterable drug exposure as measured by the area under the [Pt]filterable-time curve is greater for the extended infusions (9.6 mg X hr/L) than that for the short-term infusion (4.8 mg X hr/L). Renal excretion of cisplatin (% of dose excreted/24-hour period after the beginning of the infusion) was measured for four courses of continuous 5-day infusions and for the 30-minute infusion. Urine excretion rates were lower for the continuous infusion (5%-8% of dose/24-hour period during the infusion) compared to the short-term infusion (33% of dose/24-hour period after the beginning of the 30-minute infusion).

Chromatographic separation of the C(1), C(1a), and C(2) components of gentamicin and the assessment of their individual binding to serum proteins.

[3H]gentamicin and [14C]gentamicin samples were purified by Sephadex column chromatography and separated by an HPLC technique into the three major, medicinally active gentamicin components. These separated components were used in equilibrium dialysis studies to determine their percent binding to serum proteins. The bindings of the components were inversely related to concentrations of ionized calcium and magnesium. When dialyzed against a buffer containing physiological concentrations of the divalent cations, the binding of the C(1) component was 2.2 +/- 1.0%, the binding of the C(1a) component was 1.2 +/- 1.9%, and the binding of the C(2) component was 5.0 +/- 2.0%. The percent bindings are not identical and, due to their low values, probably have negligible clinical significance. The radioactive composition and purity of the 3H- and 14C-labeled gentamicin samples differed and these may be important factors in the variance of reported gentamicin bindings.

Effects of diethyldithiocarbamate and nickel chloride on glutathione and trace metal concentrations in rat liver.

Concentrations of reduced glutathione (GSH) and oxidized glutathione (GSSG) and 4 trace metals (Ni, Cu, Mn, Zn) were measured in livers from rats treated with sodium diethyldithiocarbamate (DDC, 0.67 or 1.33 mmol/kg, i.m.) and NiCl2 (0.25 or 0.50 mmol/kg, s.c.), singly or in combination. In rats treated with DDC or NiCl2, singly, hepatic GSH was diminished at 4 h and returned to control levels (or slightly above) at 17 h. In rats that received DDC plus NiCl2, hepatic GSH was not diminished at 4 h after increased 1.4-1.8-fold at 17 h. Hepatic GSSG was diminished at 4 h after NiCl2 treatment and returned to control values at 17 h; hepatic GSSG did not differ from control values at 4 h or 17 h after treatment with DDC, alone or combined with NiCl2. Hepatic Ni was below the detection limit (approximately 20 nmol/g) in control and DDC-treated rats; hepatic Ni was increased to 53 +/- 26 (S.D.) nmol/g at 17 h after treatment with NiCl2 alone, and was increased 6-fold (308 +/- 63 nmol/g) in rats that received Ni plus DDC. Under the same conditions, hepatic Zn was increased 33% or 41%, respectively, in rats that received NiCl2 or DDC, singly, and was not further increased by combined treatment; hepatic Cu and Mn concentrations were unaffected by NiCl2 or DDC, singly, but were diminished in rats that received NiCl2 and DDC. This study suggests: (a) that increased hepatic uptake of Ni is largely responsible for the synergistic induction of heme oxygenase activity in rats treated with NiCl2 and DDC; and (b) that increased hepatic uptake of Zn contributes to the induction of hepatic metallothionein by NiCl2 and DDC.