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J M Jaffe

Publications and source records attributed to J M Jaffe.

42 records · Page 3Linked to original sources
PubMedDate not supplied

Effect of food and an antacid on quinidine bioavailability.

Two 200 mg quinidine sulfate tablets were administered to nine healthy male subjects in the fasting state, immediately after a balanced meal, and with 30 ml of aluminum hydroxide gel using a complete crossover design. Serum and urine samples were taken over 32 and 60 h, respectively. Quinidine concentrations were measured using a high-performance liquid chromatography assay specific for quinidine. Computer fitting of the data to several models indicated that a one-compartment model with zero-order absorption and a lag time best fit all the data. Quinidine elimination and urine pH were unaffected by the study conditions. While the maximum serum concentration (Cmax) and area under the serum concentration-time curve (AUC) were unaffected by administration of quinidine with food or antacid, there was a 44 per cent increase (p less than 0.10) in time to Cmax (tmax) following quinidine administration with food. Thus, while the extent of quinidine absorption was unaffected by food or the antacid used, the rate of quinidine absorption was significantly reduced by food as reported earlier.

Adult↗
PubMedDate not supplied

Disposition of a silicon-containing amide, an inhibitor of acyl-CoA: cholesterol acyltransferase, in dog and rat.

The pharmacokinetics of 3-(decyldimethylsilyl)-N-[2-(4-methylphenyl)-1-phenylethyl]propanamide (DMPP), an inhibitor of acyl-CoA:cholesterol acyltransferase, have been studied in the dog and the rat using 14C and 3H dual-labelled drug. In both species, gastrointestinal absorption of DMPP was slow and incomplete, amounting to approximately 20 per cent of the oral dose given in corn oil. In the rat, use of PEG-400, Tween 80, ethanol, and aqueous CMC as vehicles resulted in similar or lower absorption than corn oil. Absorbed DMPP was rapidly and extensively distributed to body tissues. Data from the rat showed highest concentrations of radioactivity in the liver and spleen, while concentrations in the adrenals and lung also markedly exceeded circulating radioactivity levels. In both dog and rat. DMPP was completely metabolized prior to excretion. The routes of biotransformation involved hydrolysis of the amide bond, oxidation of the phenyl ring, and degradation of the decyldimethylsilyl propanoyl moiety. The metabolites of DMPP were excreted slowly, predominantly in the faeces. The elimination half-life of 14C was 105 h in the dog and 83 h in the rat, while that of 3H was approximately 32 h in both species.

Animals↗
PubMedDate not supplied

Influence of high-fat meal on the absorption of a silicon-containing amide, an inhibitor of acyl-CoA: cholesterol acyltransferase, in man.

The pharmacokinetics of 3-(decyldimethylsilyl)-N-[2-(4-methylphenyl)-1- phenylethyl] propanamide (DMPP), an inhibitor of acyl-CoA: cholesterol acyltransferase, have been examined in 18 healthy male volunteers who received an oral dose of either 14C-DMPP or 3H-DMPP immediately following a high-fat meal, or 3H-DMPP in the fasting state. DMPP was poorly absorbed in the fasting subjects. Administration with a high-fat meal significantly increased the extent of absorption to 15 per cent of the dose. Simultaneous fitting of the blood levels and excretion data to a pharmacokinetic model showed that ca. 64 per cent of the absorbed DMPP was metabolized while the remainder was excreted intact via the bile. The routes of biotransformation included hydrolysis of the amide bond and oxidation of the phenyl ring. The apparent volumes of distribution for DMPP and its 14C and 3H labelled metabolites were 0.89, 0.95, and 1.6 lkg-1, respectively, suggesting that these materials were distributed into extravascular spaces. The metabolites of DMPP were partially excreted in urine, accounting for 1.2 per cent and 3.8 per cent of the postprandial 14C and 3H labelled doses, respectively. The elimination half-lives of DMPP and its 14C and 3H labelled metabolites were 2.8, 5.3, and 6.9 h, respectively.

Acetyl Coenzyme A↗
PubMedDate not supplied

Interspecies similarities in the disposition of 3H-dihydroergotamine following subcutaneous administration in man and rabbits.

The disposition of dihydroergotamine methanesulfonate following single subcutaneous doses was studied in man and the rabbit using radiotracer techniques. 3H-Dihydroergotamine was almost immediately and completely absorbed from the injection site; peak blood radioactivity levels were attained within 1 h of drug administration in both species. The disappearance of radioactivity from blood was biphasic, with t 1/2,alpha and t 1/2,beta values of 2.9 and 16.9 h, respectively, in man and 2.9 and 14.7 h, respectively, in the rabbit. Apparent volumes of distribution were 18.9 Liter/kg in man and 30.4 Liter/kg in the rabbit. The excretion pattern of dihydroergotamine and its metabolites was also similar for the two species, with biliary elimination being the predominant route. At 4-5 days postdosing, 80-85% of the administered radioactivity was recovered in the feces and urine. The rabbit appears to be an adequate animal model for the study of dihydroergotamine pharmacokinetics in man.

Adult↗
PubMedDate not supplied

Effect of diet and gavage on the absorption and metabolism of fluperlapine in the rat.

Fluperlapine, Sandoz compound NB 106-689, 3-fluoro-6-(4-methyl-1-piperazinyl)-11H-dibenz[b,e]azepine, in a 12-week toxicity study exhibited liver toxicity (moderate to severe hyperlipidosis) when administered to rats in the diet at 40 mg/kg/day and at 80 mg/kg/day, but not by gavage at 80 mg/kg/day. In order to elucidate those factors which might explain these differences in toxicological findings, the effect of mode of administration (diet vs. gavage) on the absorption and metabolism was investigated in rats. Although the peak concentration of radioactivity was earlier (2 hr vs. 15 hr) and higher (3.3 micrograms eq/ml vs. 1.6 micrograms eq/ml) by gavage than by diet, the extent of absorption based on AUC values and excretion of radioactivity was the same. Analysis of plasma and liver extracts for metabolites showed that although the metabolic pathways were the same after diet or gavage, the relative composition of drug and metabolites present was a function of the mode of administration. In the liver, the target organ, after multiple oral doses by the diet mode, 96% of the identified products represented hydroxylation; a minor amount of parent drug was present. After gavage, the drug (32%) and desmethylfluperlapine (25%) together accounted for 54% of the mixture, and hydroxylation accounted for 44%. In plasma after multiple oral doses, a similar trend was observed; there was a greater percentage of the hydroxylated metabolites compared to the nonhydroxylated metabolites after diet administration and an almost similar proportion of these products after gavage administration. It is possible that the observed differences in toxicity could be due to a difference in the exposure of the target organ to drug and metabolites.

Animals↗