Jacques Dreyfuss

Metabolism of procainamide in rhesus monkey and man

Procainamide (1 Gm.) was administered orally to each of 2 cardiac patients and to 2 normal subjects. Total excretion of procainamide, its metabolites, or both in 6 hours was 19.2 and 48.8 per cent of the dose in the urine of the two patients and 57.1 and 79.5 per cent of the dose in 8 hours in the urine of the 2 normal subjects. Biologic half‐life in the plasma of 3 of the 4 human subjects ranged from 2.2 to 3.2 hours. Two metabolites were found in the pooled urine of the 4 subjects. The major metabolite has been identified as N‐acetylprocainamide; the other, as yet unidentified, has some alteration of the aromatic amino group. Procainamide•14C and N‐acetylprocainamide•14C were both administered orally at different times to 2 rhesus monkeys. Both were well absorbed; the biologic half‐life of each was about 2.5 hours. With both compounds, the radioactivity was excreted primarily in the urine (about 81 per cent of the dose) and, to a small extent, in the feces (about 6 per cent of the dose). After the administration of procainamide‐14C, the urine contained procainamide (1.7 per cent of the dose), N‐acetylprocainamide (67.6 per cent of the dose), and unidentified metabolite (3.8 per cent of the dose), and p‐acetamidobenzoic acid (2.7 per cent of the dose). After the administration of N‐acetylprocainamide‐14C, the urine contained N‐acetylprocainamide (1.7 per cent of the dose), N‐acetylprocainamide (67.6 per cent of the dose), an unidentified benzamide (5.2 per cent of the dose), and p‐acetamidobenzoic acid (3.8 per cent of the dose). Monkeys that received procainamide excreted much less unchanged drug in the urine (2.1 per cent) than did human subjects (63.6 per cent)

Metabolism of procainamide in normal and cardiac subjects

N‐Acetylprocainamide (NAPA) has been well documented as a metabolite of pro cain amide (PA) in man. The objective of the present study was to separate and quantify PA and its metabolites in man. Ten subjects (5 normal and 5 patients with heart disease) were given 40 µCi of PA−14C orally, and samples of blood, urine, and expired air were collected for 72 hr. Each subject received 500 to 1,000 mg of PA (7 to 13 mg/kg). During the 72 hr after dosing, 73% to 91% of the dose was excreted in urine. During the first 24 hr, 31% to 56% of the dose [48 ± 2.2 (mean ± SEM)] was PA; 7% to 24% (15 ± 1.8) of the dose was NAPA; 6% to 10% (7 ± 0.5) of the dose was an unknown metabolite (Rf = 0.0); and 2% to 4% (3 ± 0.2) of the dose was another unknown metabolite (Rf = 0.3). No radioactivity was detected in expired air. Less than 0.2% of the dose was accounted for as either p‐aminobenzoic acid or as p‐acetamidobenzoic acid. The maximum concentration of PA in plasma for all 10 subjects was 5.6 ± 0.9 µg/ml, 4.2 ± 0.3 µg/ml for the normal subjects and 7.1 ± 1.4 µg/ml for the patients. The T½ for the elimination of PA was 2.9 ± 0.5 hr for the normals and 5.5 ± 0.9 hr for patients. The maximum concentration of NAPA in plasma for all subjects was 2.8 ± 0.6 µg/ml, 1.6 ± 0.3 µg/ml for normal subjects and 4.1 ± 0.8 µg/ml for patients. In 2 patients, concentrations of NAPA (4.0 and 5.6 µg/ml) were as high or higher than those of PA.

Metabolism in Dogs of the Chloro- and Trifluoromethyl-Analogues of a Piperazine-substituted Dihydrobenzoxazepine

1. The comparative metabolism of the 14C-labelled 7-chloro- and 7-tri-fluoromethyl-analogues of a piperazine-substituted dihydrobenzoxazepine (4-[3-(7-(chloro or trifluoromethyl)-5,11-dihydrobenz[b,e][1,4]-oxazepin-5-yl]-1-piperazine[14C2]ethanol, dihydrochloride), SQ 11,290 and SQ 11,005 respectively, has been studied in dogs.2. After administration, both compounds were similarly excreted in urine and faeces or bile, and the radioactivity was similarly distributed in a variety of tissues. The highest concentrations of radioactivity were found in the lungs, liver, and the ocular layers consisting of the combined retina, choroid, and sclera. Similar blood levels were found for both compounds in dogs that had received equivalent doses of drug. An average of 5 or 8% of the dose was present as unchanged SQ 11,005 or SQ 11,290, respectively, in faeces, the predominant excretory route.3. Two metabolites of each compound were isolated from bile. The major metabolite, a monooxygenated derivative of the tricyclic ...

The effect of analgesics on the hexobarbital sleeping times of rats, dogs, and rhesus monkeys: A species difference

Abstract Bandol ® , (2-ethoxy- N -[2-(methylphenethylamino)-ethyl]-2,2-diphenylacetamide hydrochloride), an analgesic, increases the hexobarbital sleeping times of rats, dogs, and rhesus monkeys. The degree of increase is greater in rats than in dogs and monkeys. Darvon ® , another analgesic, increases sleeping times to about the same extent in all three animal species. In rats, Bandol is more effective than Darvon. In dogs and monkeys, Bandol is no more potent than Darvon in increasing sleeping times. Electron micrographs of sections of liver from rats that received various chronic doses of Bandol revealed some proliferation of the smooth endoplasmic reticulum. If any induction of microsomal enzymes has occurred in the rats that received Bandol chronically, other properties of the compound overshadow this effect resulting in a net increase of the hexobarbital sleeping times.

Nadolol: Placental transfer and excretion in the milk of rats

The transfer of radioactivity from maternal blood to the fetuses of pregnant rats was studied after they had been dosed orally with 100 mg/kg of [14C]nadolol (2,3-cis-5-[3-[(1,1-dimethylethyl)amino]-2-hydroxypropoxy]-1,2,3,4-tetrahydro-2,3-naphthalenediol) on Days 12, 15, and 18 of gestation. On Day 12 of gestation, during the time of organogenesis, radioactivity crossed the placental barrier to the fetuses; however, the extent of this transfer was significantly reduced on Days 15 and 18 of gestation. The excretion of radioactivity was studied in the milk of lactating rats that had been given oral 100-mg/kg doses of [14C]nadolol. Twelve or 30 hr after the dams had been dosed, radioactivity was presentin greater concentrations in milk than it was in either blood or plasma. The amount of radioactivity found in the pups that had been allowed to suckle during the intervals of 0 to 6 and 12 to 24 hr after the dams had been dosed was, for both intervals, an average of 0.041% of the dose.

In Vitro Metabolism of Dimethylaminopropylthio-cinnamanilide (SQ 16,167) and its Methylureido Analogue (SQ 11,447)

The amide bond of (trans-2′-(3-dimethylaminopropylthio)cinnamanilide (SQ 16,167), but not that of its methylureido analogue, (SQ 11,447) is cleaved in vitro by liver homogenates of the rat, dog, and human.

Species differences in the metabolism of a tricyclic psychotropic agent, SQ 11,290-14C

Abstract The metabolism of SQ 11,290- 14 C (4-[3-(7-chloro-5,11-dihydrodibenz[ b,e ]-[1,4]-oxazepin-5-yl)propyl]-α,β- 14 C 2 -1-piperazineethanol, dihydrochloride) was studied in mice, rats, guinea pigs, hamsters, New Zealand White or Dutch rabbits, monkeys and man after po administration. The excretion of SQ 11,290- 14 C, its metabolites, or both, was chiefly in the feces (with the exception of hamsters and man). Rats and rabbits of either strain excreted 2–5% of the dose—mice and hamsters excreted 20–42%—as 14 CO 2 . Hamsters appeared to excrete radioactivity in a quantitative manner most similar to that observed in man, but the metabolites found in the urine and feces of these 2 species were not similar. The disposition of SQ 11,290- 14 C in albino and pigmented rabbits cannot be distinguished on the basis of the excretion of radioactivity, but different metabolites appear to be excreted in the urine. No unchanged SQ 11,290- 14 C was detected in the excreta of humans. One percent of the dose or less was present as unchanged SQ 11,290- 14 C in the urine of any animal species. In the feces, an average of 2–6% of the dose was excreted by animal species as unchanged SQ 11,290- 14 C. Whereas albino rabbits excreted in the feces only 3.6% of the dose as unchanged drug, Dutch rabbits excreted about 16.7% of the dose as unchanged drug. In those human subjects excreting large amounts of radioactivity as 14 CO 2 , cleavage or degradation of the side chain, or both, rather than hydroxylation of the ring system as had been found previously in dogs, appeared to be a major metabolic pathway.

Metabolism of sodium tosylate-35S by rats and dogs

Sodium tosylate-35S was given po to rats (34.8 mg/kg) and po or ip to dogs (17.4 mg/kg). Both species excreted the radioactivity primarily in the urine (82–85% of the dose) and, to a lesser extent, in the feces (13–18% of the dose). Sodium tosylate-35S was rapidly absorbed by dogs after dosing po, and had a biological half-life in the plasma of 75 min. Only the unaltered tosylate-35S moiety was detected chromatographically in the excreta of both species.

Excretion and metabolism of cinanserin-14C and its oxygen analogue, SQ 10, 624-14C

Abstract Cinanserin- 14 C, trans 2′-(3-dimethylaminopropylthio)-α- 14 C-cinnamanilide hydrochloride, and its oxygen analogue, SQ 10,624- 14 C, were administered to dogs with bile fistulae. Intraduodenal admininistration of 10 mg/kg of each compound led to comparable blood and plasma levels that declined with with half-lives of 2 to 3 hr, equivalent to the rate of total excretion. During the 7-hr experiment, about 85% of each dose was eliminated in urine, bile, and expired 14 CO 2 . The radioactivity from both compounds was distributed in selected tissues in a similar manner. Although the biological disposition of cinanserin- 14 C and Sq 10,624- 14 C appears to be similar, chromatographic studies indicate that at least quantitative differences exist in the biotransformation of the two molecules. Subsequent studies with cinanserin- 14 C in rats, monkeys, and man where 14 C was present in the propyl side chain, (trans 2′-[3-dimethylamino-3- 14 C-propylthio] cinnamanilide hydrochloride) revealed significant differences between the animal species and man regarding excretion and biotransformation. Some production of 14 CO 2 was also observed in these subjects, supporting the notion of an extensive biotransformation. No more than 3% of the dose was excreted as unchanged cinanserin- 14 C by any of the animals or by humans.

Chapter 22. Drug Metabolism

Publisher Summary This chapter analyzes data concerning the metabolic fate of various classes of therapeutic agents. Agents affecting the central nervous system (CNS), particularly psychoactive agents, appear to be the most frequently studied compounds. Perazine underwent a series of metabolic transformations similar to those previously reported for other phenothiazines. Urine recovered from schizophrenic patients dosed with perazine contained N -oxide derivatives as the major nonhydroxylated metabolites, whereas this was not the case for chlorpromazine. During treatment with perazine, patients exhibited a consistent increase in the demethylated products relative to the corresponding tertiary amines, a finding attributed to the possible induction of a liver microsomal demethylase. At least 20 metabolites of imipramine excreted in human urine were identified by two-dimensional thin layer chromatography. These metabolites resulted from a combination of mono- or di-demethylation or dealkylation of the side chain and hydroxylation at the 2 or 10 positions with subsequent conjugation. The metabolism of quinidine, a naturally occurring alkaloid with antiarrhythmic properties, was studied in man as the gluconate salt. Metabolites isolated from urine were found to be oxygenated on either the quinoline or quinuclidine portions of the molecule, and uncharacterized polyoxygenated derivatives were also found.