Phase II trial of fludarabine phosphate in advanced renal cell carcinoma: an Illinois Cancer Council Study.

Fludarabine Phosphate (FP), the 2-fluoro, 5'phosphate derivative of adenosine arabinoside (ara-A), was studied in 18 patients with advanced renal cell carcinoma. These patients had measurable disease and had not received chemotherapy. FP was administered at a loading dose of 20 mg/m2 followed by a 48-hour infusion at 30 mg/m2/day given every 21 days. There were no complete or partial responses seen. Toxicity was mainly hematologic, with leukopenia most commonly observed. FP given in this manner had no activity in advanced renal cell carcinoma.

Disposition of radiolabeled imipenem and cilastatin in normal human volunteers.

In the first of two successive studies, four healthy male subjects received 500 mg of 14C-labeled imipenem alone and together with 500 mg of unlabeled cilastatin sodium. In the second study, the same subjects were given 250 mg of 14C-labeled cilastatin sodium alone and together with 250 and 1,000 mg of cold imipenem. Concentrations of imipenem and cilastatin in plasma, urine, and feces were assayed by high-pressure liquid chromatography and radiometry. Plasma concentrations of imipenem assayed radiometrically were higher than those measured by high-pressure liquid chromatography. In one subject studied at the end of drug administration, the open lactam metabolite of imipenem represented 9% of the radioactivity. Plasma levels of cilastatin determined by high-pressure liquid chromatography and radiometry were virtually identical. Urinary recovery of imipenem varied between 12 and 42% of the dose when that drug was given alone but increased to between 64 and 75% when administered with cilastatin sodium at a 1:1 ratio. Almost all radioactivity of imipenem was recovered in the urine within 96 h after drug administration. The open lactam metabolite, resulting from the metabolism of imipenem in the kidneys by a dipeptidase, dehydropeptidase-I, represented 80 to 90% of the effluent radioactivity when imipenem was given alone and about 20% when cilastatin sodium was coadministered. Renal excretion of cilastatin followed closely that of imipenem. Almost all of the administered radioactivity was recovered in 24 h, and about 75% of the dose was recovered as unchanged cilastatin within 6 h. The N-acetyl metabolite of cilastatin was found to represent about 12% of the total radioactivity.

Gas chromatographic determination of a diuretic-antihypertensive agent, (+/-)-[[6,7-dichloro-2-(4-fluorophenyl)-2-methyl-1-oxo-5-indanyl] oxy]acetic acid, in biological fluids.

A method for the measurement of a potential diuretic-antihypertensive agent, (+/-)-[[6,7-dichloro-2-(4-fluorophenyl)-2-methyl-1-oxo-5-indanyl] oxy]acetic acid, in biological fluids is described. The procedure involves the addition of a related internal standard to the specimens followed by extraction of the acids into toluene at pH 1. The indanyloxyacetic acids, following back-extraction into base and reextraction into methylene chloride at an acidic pH, are converted to methyl esters by reaction with ethereal diazomethane for subsequent gas chromatographic analysis. The sensitivity of the method is such that 5 ng of drug in 1 mL of biological specimen can be quantitated using a 63Ni electron-capture detector. The recovery from plasma in the 5-2000-ng/mL range (n = 53) was 97.0 +/- 16.3%. Differences were noted in the disposition of the enantiomers of this agent in dogs following a pharmacologically active dose.

Rapid, sensitive and specific electron capture-gas chromatographic method for the quantitation of 6-chloro-2-(1-piperazinyl) pyrazine in biological fluids.

A highly specific and sensitive gas chromatographic method for the determination of 6-chloro-2-(1-piperazinyl)pyrazine (MK-212), a central serotonin-like agent, in biological fluids is described. MK-212 and a related internal standard are extracted into benzene from an alkaline solution, back-extracted into acid and then re-extracted into benzene at an alkaline pH. The amines are converted to the trifluoroacetyl derivatives (characterized by gas-liquid chromatography-mass spectrometry), chromatographed and detected with a 63Ni electron capture detector. The sensitivity of the method is such that 10 ng of drug can be measured per aliquot of biological fluid. The precision and accuracy of the method are well within acceptable limits. Specificity of analysis was established by gas-liquid chromatography-mass spectrometry techniques.

Physiological disposition and metabolic fate of a new antiarrhythmic agent, alpha, alpha-dimethyl-4-(alpha, alpha, beta, beta-tetrafluorophenethyl) benzylamine in the rat, dog, monkey, baboon, and man.

The physiological disposition of a new orally active antiarrhythmic drug, alpha, alpha-dimethyl-4-(alpha, alpha, beta, beta-tetrafluorophenethyl)benzylamine (MK-251) was investigated in the rat, dog, rhesus monkey, baboon, and man. MK-251 was extensively absorbed after oral administration in all species. Fecal excretion was the major route of tracer elimination in the rat (70%) and dog (80%), whereas the monkey, baboon, and man excreted the majority of the dose via the urine (40-80%). MK-251 and/or its metabolites were widely distributed in rat tissues and exhibited tissue/plasma ratios greater than one in most instances. The lung, liver, and kidney possessed a high tissue affinity for drug and metabolites. The plasma and urinary profile of radioactivity indicated extensive metabolism of MK-251 in all species. Less than 5% of the plasma and urinary radioactivity was identified as unchanged drug. In spite of extensive metabolic transformations, a remarkable feature of this drug is its persistence in the plasma for long periods of time. This is thought to be due to tissue affinity. The metabolic pattern for MK-251 was essentially the same in all species. The major metabolites present in the plasma and the urine were identified as the carbinol analog of MK-251, 2-[4-(alpha, alpha, beta, beta-tetrafluorophenethyl)phenyl]-2-propanol (I), and its glucuronide conjugate. Other metabolites characterized in the urine and plasma were: the N-glucuronide of MK-251, 2-[4-(alpha, alpha, beta, beta-tetrafluorophenethyl)phenyl]propene (II), 2-nitro-2-[4-(alpha, alpha, beta, beta-tetrafluorophenethyl)phenyl]propane (III), alpha, alpha-dimethyl-4-(alpha, alpha, beta, beta-tetrafluorophenethyl)benzyl methyl ether (IV-1) and 4-(alpha, alpha, beta, beta-tetrafluorophenethyl), acetophenone (IV-2). Two minor urinary metabolites were tentatively identified as the N-hydroxy analog of MK-251 and the glycol analog of carbinol I. The in vivo formation of the methyl ether represents the first report of alkylation of a tertiary alcohol.