Plasma Lipoprotein Distribution of Liposomal Nystatin Is Influenced by Protein Content of High-Density Lipoproteins

The plasma lipoprotein distribution of free nystatin (Nys) and liposomal nystatin (L-Nys) in human plasma samples with various lipoprotein lipid and protein concentrations and compositions was investigated. To assess the lipoprotein distributions of Nys and L-Nys, human plasma was incubated with Nys and L-Nys (equivalent to 20 μg/ml) for 5 min at 37°C. The plasma was subsequently partitioned into its lipoprotein and lipoprotein-deficient plasma fractions by step-gradient ultracentrifugation, and each fraction was analyzed for Nys content by high-pressure liquid chromatography. The lipid and protein contents and compositions of each fraction were determined with enzymatic kits. Following the incubation of Nys and L-Nys in human plasma the majority of Nys recovered within the lipoprotein fractions was recovered from the high-density lipoprotein (HDL) fraction. Incorporation of Nys into liposomes consisting of dimyristoylphosphatidylcholine and dimyristoylphosphatidylglycerol significantly increased the percentage of drug recovered within the HDL fraction. Furthermore, it was observed that as the amount of HDL protein decreased the amounts of Nys and L-Nys recovered within this fraction decreased. These findings suggest that the preferential distribution of Nys and L-Nys into plasma HDL may be a function of the HDL protein concentration.     

Carbogen and nicotinamide increase blood flow and 5-fluorouracil delivery but not 5-fluorouracil retention in colorectal cancer metastases in patients.

PURPOSE: To examine whether carbogen and nicotinamide increases 5-fluorouracil (5-FU) delivery to colorectal cancer metastases. EXPERIMENTAL DESIGN: Six patients were scanned using positron emission tomography. Two scans were done to coincide with the start of separate chemotherapy cycles. At the second positron emission tomography session, 60 mg/kg nicotinamide was given orally 2 to 3 hours before 10-minute carbogen inhalation. In the middle of carbogen treatment, [15O]H2O (to measure regional tissue perfusion) and then [18F]5-FU (to measure 5-FU tissue pharmacokinetics) were administered. RESULTS: Regions of interest were drawn in 12 liver metastases, 6 spleens, 6 livers, and 12 kidneys. Nicotinamide and carbogen administration increased mean blood pO2 from 93 mm Hg (95% confidence interval, 79-198) to 278 mm Hg (95% confidence interval, 241-316; P = 0.031). Regional perfusion (mL(blood)/min/mL(tissue)) increased in metastases (mean change = 52%, range -32% to +261%, P = 0.024), but decreased in kidney (mean change = -42%, range -82% to -11%, P = 0.0005) and liver (mean change = -34%, range -43% to -26%, P = 0.031). 5-FU uptake at 3.75 minutes (m(2)/mL) increased in tumor (mean change = 40%, range -39% to +196%, P = 0.06) and decreased in kidney (mean change = -25%, range -71% to 12%, P = 0.043). 5-FU delivery measured as K1 increased in tumor (mean change = 74%, range -23% to +293%, P = 0.0039). No differences were seen in [18F]5-FU tumor exposure (net area under curve) and retention. CONCLUSION: Nicotinamide and carbogen administration can increase 5-FU delivery to colorectal cancer liver metastases. Despite an increase in perfusion and 5-FU delivery, the effects were not directly related and did not increase 5-FU retention or tissue exposure.     

The influence of lipids on stereoselective pharmacokinetics of halofantrine: Important implications in food-effect studies involving drugs that bind to lipoproteins

The objective of this study was to determine the effect of lipids on the pharmacokinetics of halofantrine enantiomers. Rats were given (+/-)-halofantrine HCl 2 mg/kg i.v., or 7 mg/kg orally. Some rats were rendered hyperlipidemic by intraperitoneal administration of poloxamer 407 1 g/kg, followed by (+/-)-halofantrine HCl intravenously. In other normolipidemic rats, (+/-)-halofantrine was administered under fasted conditions, or after peanut oil given orally. Halofantrine enantiomer plasma concentrations were considerably (>10-fold) increased in hyperlipidemia. Decreases were noted in the clearance, volume of distribution and the unbound fraction in plasma of the hyperlipidemic rats. Peanut oil caused a significant 28% reduction in clearance of the (-), but not the (+) enantiomer (mean clearance reduced 11%) of halofantrine. After oral halofantrine, peanut oil resulted in a two- to threefold increase in the plasma area under the curves of halofantrine enantiomers. Halofantrine enantiomer pharmacokinetics are highly dependent upon plasma lipid concentrations. Oral lipids may result in a stereoselective interaction at the level of clearance. Because lipids may affect clearance of drugs that bind to lipoproteins, in determining bioavailability of such drugs in food-effect studies, reference intravenous groups should be included to separate true increase in bioavailability from the effects of decreased clearance.     

Use of expandable metallic biliary stents in resectable pancreatic cancer

AIM: To compare the efficacy of metal versus plastic stents for biliary strictures in patients with surgically resectable pancreatic cancer. METHODS: The medical records at MD Anderson Caner Center from September 2001 to May 2004 were reviewed. Fifty-five patients were identified to have either a metal biliary stent (13 patients, group A) or a plastic biliary stent (42 patients, group B) and subsequently went to surgery. These two groups were compared with regards to number of stents placed prior to surgery, time period between the last stent and surgery, and operative and postoperative complications. RESULTS: Of the 13 patients in group A, 12 had pancreaticoduodenectomy performed and one had exploration only due to the peritoneal metastatses discovered at the time of surgery. Of the 12 patients with pancreaticoduodenectomy, 10 had pancreatic adenocarcinoma, 1 intraductal papillary mucinous tumor, and 1 ampullary cancer. Only 2 patients required an additional endoscopic retrograde cholangiopancreatography (ERCP) after initial metal stent placement until surgery. The average time between last stent placement and surgery was 106.5 days. Of the 42 patients in group B, 35 had pancreaticoduodenectomy and 7 had either palliative surgery or exploration due to metastatic diseases discovered at the time of surgery. Of the 35 patients, 27 had pancreatic adenocarcinoma, 5 ampullary cancer, 1 neuroendocrine tumor, 1 microcystic adenoma, and 1 autoimmune pancreatitis. Sixteen patients (38%) in group B required 3 or more ERCPs with plastic stents prior to surgery. The average time between last stent placement and surgery was 56.4 days. Preoperative chemoradiation was given to all 13 patients in group A and 31 of 42 patients in group B. There were no stent-related intra- or postoperative complications in both groups. Two of 13 patients (15%) with metal stents versus 39 of 42 patients (93%) with plastic stents, however, developed either cholangitis or cholestasis due to stent occlusion while waiting for surgery. CONCLUSIONS: Contrary to the belief that metal stents are contraindicated for patients with surgically resectable pancreatic cancer, our study demonstrated that metal stents provided a longer patency rate, fewer ERCP sessions, and fewer episodes of cholangitis without adding any intra- or postoperative complications. Therefore, metal stents should be considered for patients with resectable pancreatic cancer, especially if surgery is not immediately planned as more patients are now receiving preoperative chemoradiation.