Frederick J. Marshall

The fate of radiocarbon-labeled propoxyphene in rat, dog, and human.

Abstract Propoxyphene N -demethylation is the primary initial metabolic step in the rat. Ester hydrolysis also occurs. A large number of metabolic end products of propoxyphene are formed. They are mainly excreted in bile as conjugates. Metabolism in the dog appears to be less complex than in the rat. Norpropoxyphene and one other metabolite predominate, although several minor metabolites are present. The human differs from the rat and dog in that propoxyphene metabolites are eliminated primarily in urine rather than bile. Only one major metabolite, unconjugated norpropoxyphene, is present. This is readily isolated and characterized as the alkaline rearrangement product norpropoxyphene amide. Norpropoxyphene concentrations in human plasma are higher than those of propoxyphene. The half-life of norpropoxyphene is also substantially longer than that of propoxyphene.

The metabolism of nortriptyline-N-methyl-14C in rats

Abstract Nortriptyline, labeled with radiocarbon in the N-methyl group, has been prepared and its metabolism, distribution, and excretion studied in the rat. About 25% of an administered dose undergoes N-demethylation in the whole animal. Another 40% of the dose is excreted in urine as conjugates of the cis and trans isomers of 10-hydroxy-nortriptyline. Distribution studies demonstrate that the drug undergoes wide distribution, with the highest levels found in lung and liver. Nortriptyline was identified in the brain, showing that it does pass the blood-brain barrier; it also was found to be slowly, but efficiently, absorbed from the intestinal tract.

The metabolite pattern of d-propoxyphene in man. The use of heavy isotopes in drug disposition studies.

Abstract Through the combined use of deuterium labeling and GC-MS analysis, eight urinary metabolites of d-propoxyphene have been identified in man following a single oral dose of 130 mg of d-propoxyphene. The metabolites present were: norpropoxyphene, dinorpropoxyphene, cyclic dinorpropoxyphene, propoxyphene carbinol, norpropoxyphene carbinol, dinorpropoxyphene carbinol, p-hydroxypropoxyphene and p-hydroxynorpropoxyphene. The latter two metabolites occur as conjugates. The persistent metabolite, previously identified as norpropoxyphene, was found to be a mixture of norpropoxyphene and dinorpropoxyphene.

Isopropylbiphenyl Metabolism in the Rat. Relationships between Metabolism, Pharmacology and Toxicology

1. 4-Iso[14C]propylbiphenyl was well absorbed following either oral or intraperitoneal administration. Excretion of 14C into faeces was greater than excretion into urine. At 48 h after dosing, appreciable amounts of 14C remained in the rat carcass. 14C was found in tissues examined at 48 h, but was unusually high only in fat.2. Rats with biliary cannulae excreted about half of an oral dose in bile in 48 h.3. The principal metabolite in plasma was biphenylpropionic acid, with small amounts of biphenyl-2-propanol and biphenyl-α-methyl glycolic acid. Unchanged isopropylbiphenyl was also present.4. Metabolites in urine and bile were mainly ring-hydroxylated forms of the plasma metabolites, principally hydroxybiphenylpropionic acid and hydroxybiphenyl-2-propanol. The amount of hydroxybiphenyl-α-methylglycolic acid was unexpectedly small. All phenolic metabolites occurred as conjugates.5. Biphenylpropionic acid is probably the metabolite mainly responsible for the anti-inflammatory action of isopropylbiphenyl, ...

The Preparation of N-Methyl-C14-Labeled Drugs

In modern pharmaceutical research practice an everincreasing emphasis is being placed on studies of drug dynamics, that is, the absorption, distribution, metabolism, and elimination of an administered drug. Radiocarbon labeling can be one of the most valuable tools for such studies, provided that the drug to be studied can be synthesized containing the radiocarbon label. Fortunately, for one very large class of organic compounds of physiological interest, the N-methyl-amines, a wide variety of labeling procedures are available. Indeed, among the earliest of radiocarbon-labeled drugs to be prepared were meperidine-N-methyl-C14 (1), dimethylaminoazobenzene-N-methyl-C14 (2), and morphine-N-methyl-C14 (3).