Regional chemotherapy of neoplastic diseases

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/25399/1/0000848.pd

Determination of plasma trimetrexate levels using gas chromatography--mass spectrometry with selected-ion monitoring

Trimetrexate is a potent inhibitor of dihydrofolate reductase and has demonstrated significant antitumor activity against murine and human cell lines both in vitro and against several murine transplanted tumors. The importance of antifolate concentration and exposure time in determining toxic and therapeutic effects necessitates an assay of suitable sensitivity, accuracy and specifity for investigation of trimetrexate pharmacokinetics. This paper describes a gas chromatographic--mass spectrometric (GC--MS) procedure using selected-ion monitoring (SIM) for the determination of plasma trimetrexate levels. Using the C18 Bond-Elut extraction columns, the drug and internal standard are removed from plasma, derivatized to their bis(trimethylsilyl) derivatives and analysed by GC--SIM-MS. The reproducibility of the daily standard curves had coefficients of variation ranging from 4.9 to 11.4%. The precision of the assay yielded a coefficient of variation ranging from 5.6 to 10.1%, and the concentration means for the seeded control samples were found to be within -3.7 to +0.7% of the theoretical values for trimetrexate. No interfering peaks have been observed in application of the procedure on patient samples. The minimum detectable level under the conditions described was 0.005-0.014 [mu]M trimetrexate.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/26336/1/0000423.pd

Improved regional selectivity of hepatic arterial mitomycin by starch microspheres

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/109929/1/cptclpt1983163.pd

Sensitive high-performance liquid chromatographic method for the determination of 5-fluorouracil in plasma

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/25895/1/0000458.pd

Rapid gas--liquid chromatographic method for plasma verapamil level determination

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/25897/1/0000460.pd

Stability of trimetrexate, a new non-classical antifolate, in infusion solutions

A prerequisite for the prolonged infusion of a drug via a totally implanted drug delivery system is that the drug solution must be sufficiently stable at physiological temperatures to endure the time intervals between drug replacement or pump refills. Consequently, the stability of the chemotherapeutic agents can influence the dosing accuracy and ultimately the achievement of the desired therapeutic goal. The chemical stability of the pharmaceutical preparation Trimetrexate (TMQ) glucuronate, a non-classical, lipophilic antifolate, has been characterized. Incubation of TMQ (prepared in sterile water to a concentration of 5.0 mg/ml) in sterile, amber glass vials at 37[deg]C for 56 days resulted in a degradation rate constant of 0.0134 +/- 0.002 day-1 and a half-life of 51.6 +/- 0.8 days. The major degradation product has been identified as (2,4-diamino-5-methyl-6-carboxyaldehyde)quinazoline. Ten percent TMQ degradation would occur by 7.9 days of incubation under these conditions.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/29273/1/0000332.pd

Constant intraperitoneal 5‐fluorouracil infusion through a totally implanted system

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/109794/1/cptclpt198412.pd

High-performance liquid chromatographic method for the determination of bromodeoxyuridine and its major metabolite, bromouracil, in biological fluids

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/25867/1/0000430.pd

Disposition of WR-1065 in the liver of tumor-bearing rats following regional vs systemic administration of amifostine

Purpose —Amifostine is a prodrug in which selectivity is largely determined by the preferential formation and uptake of its cytoprotective metabolite, WR-1065, in normal tissues as a result of differences in membrane-bound alkaline phosphatase activity. It was hypothesized that amifostine may be a good candidate for regional drug delivery to the liver because of its large hepatic extraction and total body clearance. Methods —Rat livers were implanted with Walker-256 tumors. The tumor-bearing rats received 15 min infusions of amifostine (200 mg/kg) via the portal vein or the femoral vein. WR-1065 concentrations in the blood, liver and tumor were measured at various times. Results —The WR-1065 tumor portal dosing AUC 15−60 was 40% of systemic dosing, and tumor concentrations following portal dosing were one-fifth of that following systemic dosing. The portal dosing WR-1065 liver AUC 15−60 was 60% higher than the values for systemic dosing. The liver/tumor concentration ratios of WR-1065 following portal dosing were up to 8-fold higher than the ratio following systemic administration. Unfortunately, systemic exposure to WR-1065 was greater following portal vs systemic amifostine. Conclusions —Amifostine may provide increased liver protection and decreased tumor protection from radio- or chemotherapy when administered by the portal vein. However, portal dosing also increases systemic exposure to WR-1065, which is associated with hypotension. Copyright © 2004 John Wiley & Sons, Ltd.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/34602/1/380_ftp.pd