Improved oral delivery of N-(4-hydroxyphenyl)retinamide with a novel LYM-X-SORB organized lipid complex.

Purpose: Fenretinide [N-(4-hydroxyphenyl)retinamide (4-HPR)] is a cytotoxic retinoid that suffers from a wide interpatient variation in bioavailability when delivered orally in a corn oil capsule. The poor bioavailability of the capsule formulation may have limited responses in clinical trials, and the large capsules are not suitable for young children. To support the hypothesis that a novel organized lipid matrix, LYM-X-SORB, can increase the oral bioavailability of fenretinide, fenretinide in LYM-X-SORB matrix and in a powderized LYM-X-SORB formulation was delivered to mice.

Effect of an organized lipid matrix on lipid absorption and clinical outcomes in patients with cystic fibrosis.

Objectives: To compare the absorption of a lysophosphatidylcholine, monoglyceride, and fatty acid matrix (organized lipid matrix, OLM) with that of a triacylglycerol (TG)-based fat meal in patients with cystic fibrosis (CF).

Study Design: Five adolescents with CF and 3 control patients were given fat meals supplemented with retinyl palmitate of either OLM or TG at a 2-week interval. In a clinical trial, 73 patients with CF were randomly assigned to nutritional supplements containing either OLM or TG for a 1-year double-blind trial followed by a 6-month observation period.

Development, evaluation and use of a pharmacokinetic model for hexachlorobenzene.

This study discusses the background, biological basis, development characteristics, application and evaluation of six physiologically based multicompartment models that describe the absorption, distribution and elimination of hexachlorobenzene (HCB) in growing rats and growing humans. The models for rats and for humans have similar structures but differ in specific physiological parameters. The goal of the modelling effort was to obtain toxicological information about HCB based on its pharmacokinetics.

Human disposition and some biochemical aspects of methylxanthines.

The human disposition of caffeine, theophylline, and theobromine is essentially characterized by rapid and complete gastrointestinal absorption; minimal first pass metabolism; distribution throughout the total body water; extensive and, in the case of caffeine almost complete, biotransformation in the liver; and elimination of metabolites from the body via the kidneys. Methylxanthine metabolism is affected by such factors as diet, smoking, pregnancy, use of oral contraceptives, age, and disease state. These factors have been studied extensively in relationship to caffeine disposition, less so for theophylline, and minimally for theobromine as well as the metabolites of these compounds, in particular paraxanthine and the diaminouracils.

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.

Human metabolism of [1-methyl-14C]- and [2-14C]caffeine after oral administration.

Radiolabeled caffeine was administered orally at 5 mg/kg to adult, male volunteers. Blood, saliva, expired CO2, urine, and feces were collected and analyzed for total radiolabeled equivalents, caffeine, and its metabolites. High-performance liquid chromatography (HPLC) was the principal technique used to separate caffeine and the various metabolites with quantitation by liquid-scintillation counting.

Comparative physiological disposition of N-(phosphonacetyl)-L-aspartate in several animal species after intravenous and oral administration.

The physiological disposition of N-(phosphonacetyl)-L-aspartate (NSC 224131; PALA), a potent inhibitor of aspartate transcarbamylase, has been studied in mouse, rat, dog, and monkey after administration of [14C]PALA at 120 mg/sq m i.v. or p.

The effect of coffee consumption on plasma lipids, lipoproteins, and the development of aortic atherosclerosis in rhesus monkeys fed an atherogenic diet.

Rhesus monkeys (seven females and six males) were fed ad libitum a diet comparable to that consumed by humans, containing 25% by weight fat (40% of calories) and 0.15% cholesterol (0.3 mg/kcal) for 12 months (phase 1).

Binding of the Cain quinolinium, NSC 113089, to rat tissue lipid extracts.

The binding characteristics of the cancer chemotherapeutic Cain's quinolinium 6-amino-1-ethyl-4-[p-[[p-[(1-ethylpyridinium-4-yl) amino] phenyl] carbamoyl]-anilino]-quinolinium dibromide (NSC 113089) to lipid extracts from rat kidney, liver, heart and skeletal muscle has been studied. Such binding is saturable with an apparent KD congruent to 1.6 microM.

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.

Pharmacokinetic considerations in evaluating the effects of tetrahydrouridine on 5-azacytidine chemotherapy in L1210 leukemic mice.

The pharmacokinetics of 5-azacytidine (5-azaCR) and tetrahydrouridine (THU) were considered in evaluating the effect of THU on chemotherapy with 5-azaCR in L1210 leukemia mice. The administration of three different dose levels of THU and 5-azaCR ip in either a 6- or 72-hour infusion gave minimal increases in therapeutic effect. At the high-dose combinations (except in the 72-hour infusion), THU appeared to enhance toxicity.

Metabolism of daunomycin (NSC-82151) in vitro and the chemotherapeutic activity of isolated metabolites in vivo.

Daunomycin (D1) was quantitatively converted to a metabolite, D2 (> 98% conversion), by an aerobic, cell-free system containing nicotinamide adenine dinucleotide phosphate, reduced form (NADPH) and the 100,000 x g supernatant fluid of rat kidneys. Under lowered oxygen concentrations, cell homogenates plus NADPH converted D, quantitatively to an unknown metabolite, D(x), with D2 as a possible intermediate. The chromatographic properties of D(x) differed from those of D2 and the aglycones of D1 and D2 (D4 and D3 respectively).