Characterization of diaminouracil metabolites of caffeine in human urine.

A major caffeine metabolite (A1) has been isolated from human urine by a combination of solvent extraction, reverse phase high-pressure liquid chromatography, and silica gel open column chromatography. The chromatographic and spectral properties of A1 are identical with an authentic sample of 5-acetylamino-6-amino-3-methyluracil. A stable isotope-labeling study, in which [2-14C]caffeine in a 1:1 mixture of unlabeled caffeine and [1,3-15N-8-13C] caffeine was administered to subjects, demonstrated that the C-8 carbon of caffeine was lost during the biotransformation to A1.

A phase I trial of combination therapy with continuous-infusion PALA and continuous-infusion 5-FU.

Thirty-four patients were treated with N-(phosphonacetyl)-L-aspartate (PALA) at a dose of 850 mg/m2/day x 5 by continuous intravenous infusion (days 1-5) and 5-fluorouracil (5-FU) on an escalating dose schedule of 300-630 mg/m2/day x 5 by continuous intravenous infusion (days 2-6). Dose-limiting oral mucositis occurred at a 5-FU dose of 560 mg/m2/day; other toxicities included nausea, vomiting, diarrhea, skin rash, and superficial venous phlebitis. Myelosuppression was rare.

Quantitation of the antitumor agent N-(phosphonacetyl)-L-aspartic acid in human plasma and urine by gas chromatography-mass spectrometry-selected ion monitoring.

N-(Phosphonacetyl)-L-aspartic acid (PALA) is an antitumor agent which is currently under clinical study. A gas chromatography--mass spectrometry--selected ion monitoring assay procedure using [13C]PALA as the internal standard has been developed for the quantitation of PALA in biological samples. Standard curves which related ion intensity peak height ratios (m/e 220/221) to PALA concentrations in plasma and urine were described by a non-linear least square analysis with correlation coefficients of R2 greater than 0.

Characterization of the metabolites of ellipticine in rat bile.

The two major metabolites of ellipticine (NSC 71795) were isolated from rat bile by a combination of solvent extraction, partition column chromatography, and reverse phase high-performance liquid chromatography. Purification and structural elucidation of the bile products were aided by administration of the drug with a dual label (14C and 2H). The two metabolites were shown to be the sulfate and glucuronide conjugates of 9-hydroxyellipticine by chemical, enzymatic, and mass-spectral fragmentation comparison with synthetic and enzymatically prepared reference compounds.

A new class of antimalarial drugs: derivatives of benzothiopyrans.

A series of substituted benzothiopyrans was synthesized and examined for antimalarial activity. Some were found to be active and curative at dose levels of 160--360 mg/kg against Plasmodium berghei in mice. Afew observations concerning structure-activity relationships were made.

Aromatic hydroxylation of ellipticine in rats: lack of an NIH shift.

Metabolites of the antitumor agent, elipticine (NSC) 71795), are mainly secreted in rat bile as two conjugates of hydroxylated elipticine. The possible involvement of an arene oxide intermediate prior to hydroxylation and conjugation has been studied using 7,9-dideutero-ellipticine and by determining the conservation of deuterium in the phenolic products. The deuterated drug was synthesized by acid catalyzed exchange and was characterized by nuclear magnetic resonance and high and low resolution mass spectrometry.