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In patients with pseudomyxoma peritonei or peritoneal mesothelioma, direct extension of disease through the hemidiaphragm may result in an isolated progression of tumor within the pleural space. We monitored the intrapleural and plasma levels of mitomycin C and doxorubicin by HPLC assay in order to determine the pharmacokinetic behavior of this intracavitary use of chemotherapy. Our results showed a persistent high concentration of intrapleural drug as compared to plasma concentrations. The increased exposure for mitomycin C was 96, and the increased exposure for doxorubicin was 241. When the clearance of chemotherapy from the thoracic cavity was compared to clearance from the abdomen and pelvis, there was a considerably more rapid clearance from the abdomen as compared to the thorax. The pharmacologic study of intrapleural chemotherapy in these patients provides a strong pharmacologic rationale for regional chemotherapy in this group of patients. [ABSTRACT FROM AUTHOR]

The peritoneal surface remains an important failure site for patients with gastrointestinal and gynecologic malignancies. During the last 2 decades, novel therapeutic approaches, combining cytoreductive surgery with intraoperative intracavitary and intravenous chemotherapy, have emerged for peritoneal carcinomatosis patients. This has resulted in remarkable clinical successes in contrast with prior failures. Although further clinical data from phase II and III trials supporting this combined treatment protocols are necessary, an optimalization of the wide variety of different perioperative cancer chemotherapy protocols used in these treatment regimens is equally important. To this date, a clear understanding of the pharmacology of perioperative chemotherapy is still lacking. The efficacy of intraperitoneal cancer chemotherapy protocols is governed as much by nonpharmacokinetic variables (tumor nodule size, density, vascularity, interstitial fluid pressure, and binding) as by the pharmacokinetic variables (dose, volume, duration, pressure, and carrier solution). Our recent data support the importance of the tumor nodule as the most meaningful pharmacologic end point. Timing of perioperative intravenous chemotherapy may substantially influence the pharmacokinetics. This review aims to clarify the pharmacokinetic and pharmacodynamic data currently available regarding the intraperitoneal delivery of cancer chemotherapy agents in patients with peritoneal carcinomatosis. [ABSTRACT FROM AUTHOR]

Purpose. To measure the clearance intraperitoneal mitomycin C and doxorubicin in patients having peritonectomy and analyze the impact of the extent of peritoneal resection on pharmacokinetics. Methods. A group of 15 patients with peritoneal carcinomatosis were submitted to cytoreductive surgery and heated intraperitoneal chemotherapy. Ten patients received mitomycin C and five, doxorubicin. Six patients underwent total parietal peritonectomy and nine had less-extensive peritonectomy. Pharmacokinetics were determined by sampling peritoneal fluid and blood. Drug concentrations over time, area under the curve ratios and the amount of drug recovered from the peritoneal cavity were calculated and compared between the groups. Results. The concentrations of mitomycin C over time in the peritoneal fluid and plasma were similar in five patients with total parietal peritonectomy as compared to five patients with less-extensive peritonectomy (P=0.5350 and 0.6991; Mann-Whitney test). Mitomycin C area under the curve ratio in total peritonectomy patients was 20.5 and 25.7 in patients with less-extensive peritonectomy. The difference in total amount of drug recovered from the peritoneal cavity was not significant (30.6±6.188% versus 22.6±3.84%, P=0.095). In the studies with doxorubicin, one patient underwent total parietal peritonectomy with similar pharmacokinetics to four patients submitted to partial peritonectomy. Conclusions. The extent of parietal peritoneal resection did not affect the pharmacokinetics of intraoperative intraperitoneal chemotherapy. The pharmacological barrier between the abdominopelvic cavity and plasma is not directly related to an intact peritoneum. [ABSTRACT FROM AUTHOR]

Purpose. Docetaxel (Taxotere) has been shown to possess a broad spectrum of antitumor activity against various malignancies such as breast and lung cancers, but also against intraabdominal malignancies such as mesothelioma and ovarian cancer. For cancers occurring within the abdominal cavity, the advantage of intraperitoneal chemotherapy is the prolonged 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 distribution of intraperitoneal versus intravenous docetaxel. Methods. The study animals were comprised of 15 Sprague Dawley rats. They were randomized into three groups according to dose and route of administration (15 mg/kg intravenously, 15 mg/kg intraperitoneally, or 150 mg/kg intraperitoneally) and then given a single dose of docetaxel. Blood and peritoneal fluid were sampled using a standardized protocol for 90 min. At the end of the procedure the rats were killed and docetaxel concentrations in peritoneal fluid, plasma and selected tissue samples were determined by high-performance liquid chromatography (HPLC). Results. When docetaxel was delivered at 15 mg/kg the area under the curve (AUC) of the peritoneal fluid was significantly higher with intraperitoneal administration (110.6 µg/ml·min) as compared to intravenous administration (0.043 µg/ml·min; P=0.0079). This represents more than a 2500-fold increase in exposure for tissues at peritoneal surfaces after intraperitoneal administration. Conversely, at the same dose the AUC of the plasma was significantly lower with intraperitoneal administration (0.11 µg/ml·min) as compared to intravenous administration (4.25 µg/ml·min; P=0.0079). The AUC ratio (AUC peritoneal fluid/AUC plasma) was 976 for intraperitoneal administration as opposed to 0.01 for intravenous delivery. The AUC ratio for intraperitoneal docetaxel at 150 mg/kg was 3004. There were significantly different concentrations in the heart and the abdominal wall (P=0.0079) and in the stomach and colon (P=0.0159) when intraperitoneal versus intravenous docetaxel were compared. Conclusions. The exposure of the peritoneal surface to docetaxel is significantly increased and the systemic exposure decreased with intraperitoneal docetaxel administration. Also, high concentrations of drug were observed in the abdominal wall and in the colon after intraperitoneal delivery. This experiment suggests the need for clinical studies to evaluate intraperitoneal administration of docetaxel in humans. [ABSTRACT FROM AUTHOR]

Purpose: In the treatment of gastrointestinal malignancies with dissemination to peritoneal surfaces the principal advantage of intraperitoneal chemotherapy over intravenous chemotherapy is the high drug concentration achieved locally with low systemic toxicity. This advantage can be optimized by maintaining a large area of contact between the chemotherapy solution and the surfaces within the abdomen and pelvis over a prolonged time period. Using a rat model we compared the pharmacokinetics of two drugs infused intraperitoneally, 5-fluorouracil and gemcitabine, in five different carrier solutions.Methods: A total of 120 Sprague Dawley rats were randomized into groups according to the carrier solution and the drug administered. Rats were given a single dose of intraperitoneal 5-fluorouracil (20 mg/kg) or gemcitabine (12.5 mg/kg) in 0.1 ml/g body weight of each carrier solution. The carrier solutions used varied in their tonicity (0.3%, 0.9% or 3% sodium chloride), or were isotonic and varied in molecular weight (0.9% sodium chloride, 4% icodextrin and 6% hetastarch). With the hypotonic, isotonic and hypertonic sodium chloride solutions, only 5-fluorouracil was used. Each group was further randomized according to the intraperitoneal dwell period (1, 3 or 6 h). At the end of the procedure the rats were killed, the peritoneal fluid was withdrawn completely and the blood was sampled using a standardized protocol. The volume of the peritoneal fluid was recorded, and the drug concentrations in the peritoneal fluid and plasma were determined by high-performance liquid chromatography.Results: Measurements of peritoneal fluid volume showed a more rapid clearance of hypotonic and isotonic sodium chloride solutions from the peritoneal cavity as compared to hypertonic sodium chloride and high molecular weight solutions. When comparing the remaining intraperitoneal volumes at 6 h, the differences were statistically significant for both 5-fluorouracil and gemcitabine when hetastarch (P < 0.0001 and P = 0.0004) and icodextrin (P = 0.002 and 0.008) were compared with isotonic sodium chloride solution. Similarly, there was a significant difference in the volumes recorded at 6 h when hypotonic (P < 0.0001) and isotonic sodium chloride solutions (P = 0.0002) were compared with hypertonic sodium chloride solution. The concentrations of chemotherapy in the different carrier solutions varied little. The total amount of drug in the peritoneal cavity decreased with all solutions and more quickly with 5-fluorouracil than with gemcitabine. There was a significant difference in the total intraperitoneal 5-fluorouracil between hypotonic and isotonic sodium chloride solutions at 1 h (P = 0.0003) and 3 h (P = 0.0043), as well as between the isotonic and hypertonic sodium chloride solutions at 1 h (P = 0.03) and 3 h (P < 0.0001). Similarly, there was a significant difference in the total peritoneal gemcitabine at 6 h between icodextrin and isotonic sodium chloride solution (P = 0.01) and between hetastarch and isotonic sodium chloride solution (P = 0.05). There were no significant differences in plasma 5-fluorouracil and plasma gemcitabine concentrations obtained with the five solutions.Conclusions: These findings show that the clearance of 5-fluorouracil and gemcitabine from the peritoneal cavity can be significantly modified by varying the tonicity or the molecular weight of the carrier solution. Peritoneal fluid clearance was slower with hypertonic sodium chloride and high molecular weight solutions and this resulted in a reduced clearance of chemotherapy. By using a high molecular weight carrier solution the exposure of intraperitoneal cancer cells to gemcitabine was prolonged and drug availability at the peritoneal surface was increased. Similarly, by using a hypertonic carrier solution the exposure to 5-fluorouracil was prolonged and drug availability at the peritoneal surface was also increased. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this study was to report the pharmacokinetics of heated intraoperative intraperitoneal mitomycin C (MMC) and to analyze the impact of heat, extent of peritoneal resections, and effect of intraoperative hyperthermic chemotherapy on the pharmacological properties of the peritoneal plasma barrier. Methods: Sixty patients with peritoneal carcinomatosis were included in a phase I/II study combining cytoreductive surgery with 2 h of heated intraperitoneal mitomycin C in an intraoperative lavage technique and one cycle of early postoperative 5-fluorouracil (5-FU) given on postoperative days 1–5. Three pharmacokinetic analyses were performed: (1) pharmacokinetics of heated intraoperative intraperitoneal MMC was determined for 18 patients by sampling peritoneal fluid, plasma, and urine during the 2-h procedure; (2) impact of peritoneal resections on MMC pharmacokinetics was assessed by comparing a group of patients who underwent ≤1 peritonectomy procedure (minimal surgery) to a group of patients who underwent ≥2 peritonectomy procedures (extensive surgery), and (3) effects of heated intraoperative intraperitoneal chemotherapy on the pharmacokinetics of early postoperative intraperitoneal 5-FU by comparing a group of patients treated with heated intraoperative intraperitoneal MMC to a control group who did not receive heated intraoperative intraperitoneal chemotherapy. Results: The mean dose of heated intraoperative intraperitoneal MMC per patient was 22.5 ± 7.1 mg (12.9 ± 3.8 mg/m[sup 2] ). Drug absorption from perfusate was 14.3 ± 2.7 mg. The mean aeras under the curve (AUC) for perfusate and plasma were, respectively, 340 ± 138 and 15 ± 4 µg/ml × min. The mean AUC peritoneal fluid/plasma ratio was 23.5 ± 5.8. Patients who underwent extensive peritoneal resections exhibited a significantly (p = 0.037; Wilcoxon rank test) increased peak plasma concentration of MMC, a significantly (p = 0.029) increased AUC of plasma concentrations and a significantly (p = 0.034) decreased peritoneal fluid/plasma AUC ratio. Pharmacokinetic studies of early postoperative intraperitoneal 5-FU showed no significant difference in plasma AUC, perfusate AUC and AUC ratio between patients who received and those who did not receive heated intraoperative intraperitoneal MMC. Conclusions: Heated intraoperative intraperitoneal chemotherapy achieves high peritoneal concentrations of MMC with limited systemic absorption. Systemic drug absorption during heated intraoperative intraperitoneal chemotherapy is increased when extensive peritoneal resections are performed, but such slight increases are unlikely to change the risk of systemic drug toxicities. Heated intraoperative intraperitoneal chemotherapy does not alter the pharmacokinetics of early postoperative intraperitoneal 5-FU. [ABSTRACT FROM AUTHOR]

In this article, the authors discuss various articles on pharmacokinetics during intrapertieoneal chemotherapy published in this issue of the periodical.

: BackgroundIntraperitoneal chemotherapy administration results in high drug concentration locally with low systemic toxicity. Using a rat model we compared the pharmacokinetics and tissue absorption of docetaxel infused intraperitoneally in two isotonic carrier solutions; 1.5% dextrose peritoneal dialysis solution (peritoneal dialysis solution) and hetastarch (6% hydroxyethyl starch), a high molecular weight solution.: Materials and methodsSixty Sprague–Dawley rats were randomized into groups according to the carrier solution administered. Rats were given a single dose of intraperitoneal docetaxel (80 mg/m2) in 0.1 ml/g body weight of each carrier solution. Each group was further randomized according to the intraperitoneal dwell period (3, 6, 12, 18, and 24 h). At the end of the procedure the rats were killed, the peritoneal fluid was withdrawn completely and the volume recorded. Blood and tissues were sampled using a standardized protocol. Drug concentrations in peritoneal fluid, plasma, and tissues were determined by high-performance liquid chromatography.: ResultsHetastarch clearance from the peritoneal cavity was reduced when compared to peritoneal dialysis solution. The mean volumes remaining in the peritoneal cavity were significantly higher with hetastarch at 6 h (P = 0.022) and 12 h (P = 0.0012). Plasma docetaxel concentrations were similar for both carrier solutions. The mean total amount of docetaxel remaining in the peritoneal cavity was significantly greater with hetastarch at 3 h (P = 0.0022), 6 h (P = 0.0043), and 12 h (P = 0.0023). There was a 39% increase in the area under the curve ratio of peritoneal fluid to plasma docetaxel concentrations with hetastarch (227) versus peritoneal dialysis solution (163). Docetaxel concentrations were significantly greater with hetastarch in colonic tissue at 18 and 24 h, and in gastric tissue at 6, 12, and 18 h.: ConclusionThe use of intraperitoneal docetaxel with a hetastarch carrier solution provides a pharmacologic advantage for a local-regional killing of residual intraperitoneal tumor cells without increasing systemic toxicity. [Copyright &y& Elsevier]