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Biomedical subjects

B H Migdalof

Publications and source records attributed to B H Migdalof.

At least 37 records · Page 2Linked to original sources
PubMed1981

Absorption and bioavailability of captopril in mice and rats after administration by gavage and in the diet.

The absorption of captopril (I), a new antihypertensive agent, was studied in mice and rats at doses (50 and 1350 mg/kg) administered in the diet in chronic toxicological studies. 3H- or 35S-Labeled I was administered by gavage and in the diet to male and female animals in a two-way crossover study. Animals received daily doses of nonradiolabeled I in the diet for 25 days, except on Days 15 and 22 when radiolabeled I was administered either by gavage or in the diet. Absorption of the total radioactivity in 2-month-old mice averaged 49 and 48%, respectively, of the 50- and 1350-mg/kg doses given in the diet and 57 and 65%, respectively, of the doses given by gavage. The bioavailability of I in 2-month-old mice averaged 48 and 39% (diet) and 44 and 59% (gavage) of the 50- and 1350-mg/kg doses, respectively. In 2-month-old rats, absorption of the total radioactivity averaged 41% of the 50-mg/kg dose given in the diet. In 2- and 15-month-old rats, minimum absorption of the 1350-mg/kg dose averaged 36 and 45% (diet) and 51 and 71% (gavage), respectively; the minimum bioavailability averaged 20 and 29% (diet) and 39 and 44% (gavage), respectively. These studies demonstrate adequate absorption and bioavailability of I over a wide range of doses from the drug-diet mixtures and by young and old animals and also illustrate a useful experimental design for the estimation of relative oral absorption of a drug administered continuously in the diet over several days.

Animals↗
PubMed1981

Pharmacokinetics of captopril in dogs and monkeys.

[14C]Captopril was given as a priming dose, followed by constant intravenous infusion for 4 or 6 hr, to three anesthetized dogs and three anesthetized monkeys. Blood, urine, and bile samples were collected during and after drug infusion. Pharmacokinetic evaluations were carried out exclusively on data obtained for unchanged captopril. The average total body clearance (ClT) and the renal clearance (ClR) of captopril, in milliliters per kilogram per hour, were 605 and 341 in the dog and 1135 and 944 in the monkey. The biliary clearance of captopril was negligible in both species. The greater difference between the ClR and ClT values in the dog compared to that in the monkey was the result of more extensive metabolism of captopril by the dog. Since almost all of the radioactive dose was recovered in urine in both species, captopril and its metabolites were almost exclusively eliminated by the kidneys. One primary reason that body and renal clearance values of captopril were much greater in the monkey than in the dog was that the net tubular secretion fo captopril was about three times greater in the monkey (82%) than in the dog (28%). The volume of distribution of captopril was higher in the monkey (3.6 liters/kg) than in the dog (2.6 liters/kg); the volume of the central compartment was about the same (0.5 liter/kg) for both species. The terminal half-life value was slightly higher in the dog (2.8 hr) than in the monkey (2.2 hr).

Anesthesia↗
PubMed1980

Disposition of captopril in normal subjects.

The disposition of captopril, an angiotensin-converting enzyme inhibitor with antihypertensive properties, was studied in 10 normal male subjects after a single 100-mg tablet of 35S-labeled drug. Average absorption parameters for unchanged captopril in blood were Tmax 0.93 +/- 0.08 hr and Cmax 800 +/- 76 ng/ml. For total radioactivity in blood the values were Tmax 1.05 +/- 0.08 hr and Cmax 1,580 +/- 90 ng/ml (as captopril equivalents). Because of the curvilinearity of the semilogarithmic plots of blood concentrations of captopril:time, elimination half-life (t1/2) of unchanged drug could not be determined. At 1 hr unchanged captopril accounted for about 52% of total radioactivity in blood, and the dimeric disulfide metabolite of captopril accounted for about 10%. In the first 5 days after dosing, an average of about 68% of the radioactive dose was recovered in urine and 18% in feces. The distribution of radioactivity in the first 24-hr urine sample (66% of the dose) was 58% captopril (38% of dose), 2% captopril disulfide (1.5% of dose), and 40% unidentified polar metabolites (26% of dose).

Absorption↗
PubMed1979

Absorption and excretion of tolmetin in arthritic patients.

The absorption, kinetics, biotransformation, and excretion of tolmetin and its metabolites were studied in patients with rheumatoid arthritis (RA) to evaluate the effects of the disease on tolmetin disposition. Five RA patients were stabilized on tolmetin sodium (300 mg, 4 times daily for 14 days) before receiving a single oral solution dose of tolmetin-14C sodium (300 mg as the acid) on day 15. Tolmetin was rapidly and completely absorbed (peak time, 20 to 60 min) and eliminated rapidly from plasma with a biphasic decay curve (t1/2beta congruent to 2.1 hr). MCPA, the oxidative metabolite, appeared more slowly (peak time, 40 to 90 min) but was eliminated rapidly in a biphasic manner (t1/2beta congruent to 1.7 hr). The terminal elimination phases for both tolmetin and MCPA demonstrated a curvature which suggested possible nonlinearity in the kinetic disposition of the drug. There were no apparent effects of the disease on the kinetics of tolmetin or MCPA. Tolmetin, MCPA, and tolmetin glucuronide were recovered quantitatively in urine (0 to 72 hr) with most of the exretion occurring in the 0- to 24-hr period. A significant increase, relative to data on normal subjects, in the renal clearance of both tolmetin and MCPA was noted. Concomitant increase in the apparent volume of distribution secondary to reported decreases in the plasma protein binding of tolmetin appeared to be the reason for increased renal clearance of tolmetin.

Arthritis, Rheumatoid↗
PubMed1979

Penfluridol: a neuroleptic drug designed for long duration of action.

1. Penfluridol is a unique, long-acting, oral neuroleptic belonging to the diphenylbutylpiperidines. The synthesis of penfluridol represented the result of a well-planned scientific search for a highly lipophilic compound structurally related to haloperidol and pimozide. 2. Because of its unusual lipophilicity, penfluridol distributes extensively in fatty tissues following oral administration. This depot effect produces a very slow release of drug from the tissues, and results in a very long duration of activity. 3. Penfluridol is extensively metabolized by oxidative N-dealkylation to afford, as isolated metabolites, the beta-glucuronide conjugate of the diphenylbutyric acid derivative A1 and the unconjugated basic piperidine moiety B1. It is assumed, at this time, that the pharmacological activity is attributable to the parent compound. 4. When administered clinically at oral doses of 20 to 100 mg/week, penfluridol has been found to be an effective antipsychotic agent. This frequency of dosing is consistent with the pharmacokinetic behavior of the drug in man, and does not appear to result in any inappropriate accumulation of the drug in patients. Wide variations in steady-state levels and plasma elimination half-life have been observed in patient populations.

Animals↗
PubMed1979

Renal handling of zomepirac sodium (McN-2783-21-98) in the rat.

The plasma and renal clearance of zomepirac, a weak organic acid, was investigated in anesthetized CR Wistar rats after administration of single bolus i.v. injections or continuous i.v. infusions of the 14C-labeled compound. Adjustment of urine pH to the alkaline range caused more than an 8-fold lowering of the plasma elimination half-life (from 7.0 to 0.8 hr) and enhanced renal clearance by a factor of 53 compared to control. Acidification of the urine or probenecid administration increased the elimination half-life (to 10.9 and 17.5 hr, respectively), and decreased renal and plasma clearance of zomepirac. Since zomepirac is highly bound to plasma proteins (approximately 98%), only a small fraction of the drug is available for filtration at the glomerulus. Therefore, the renal elimination of zomepirac is accomplished mainly by active tubular secretion. Passive nonionic reabsorption is a major factor in determining the net clearance of the drug.

Animals↗
PubMedDate not supplied

Effect of food on the bioavailability of captopril in healthy subjects.

14C-Captopril was administered as 100-mg tablets to 12 subjects in a two-way crossover study in which subjects were either fasted or were given a standard meal immediately prior to dosing. Based on blood level and urinary excretion data, both the absorption of total radioactivity and the bioavailability of captopril were decreased approximately 35 to 40 per cent after a meal. Whether this moderate decrease in the absorption and the bioavailability of captopril caused by food is of clinical significance has not yet been determined.

Adolescent↗
PubMedDate not supplied

The time course of tolmetin and its metabolites in the plasma of individual rats and mice.

Tolmetin, 1-methyl-(5-p-toluoyl)pyrrole-2-acetic acid, is a new, nonsteroidal, anti-inflammatory agent. After oral administration of tolmetin-14C to rats and mice, sequential microsamples of blood were obtained from the ophthalmic venous plexus via the orbital sinus. Plasma was collected after centrifugation, and microaliquots of each plasma sample were analyzed. The total radioactivity and thin-layer chromatographic assays used permitted quantitation of tolmetin, its dicarboxylic acid metabolite, and (by difference) all other metabolites collectively for each sample. Time-course data on plasma levels were obtained for individual rats and mice. The plasma elimination half-life of tolmetin was estimated at 0.67 +/- 0.13 hr (mean +/- SD) in male rats, 1.4 +/- 0.6 hr in female rats, 1.2 +/- 0.3 hr in male mice, and 1.0 +/- 0.0 hr in female mice. A one-compartment open model was used.

Administration, Oral↗
PubMedDate not supplied

Relative contribution of the gut, liver, and lung to the first-pass hydrolysis (bioactivation) of orally administered 14C-fosinopril sodium in dogs. In vivo and in vitro studies.

The relative contribution of the gut, liver, and lung to the first-pass hydrolysis (bioactivation) of the orally administered prodrug, fosinopril sodium (FS), to the active angiotensin-converting enzyme (ACE) inhibitor, SQ 27,519 (S), was determined. Two dogs each received 14C-FS by the following routes of administration: oral, intraportal, and intra-arterial. Extraction ratios (E) for the gut and liver were calculated based on the relative ratios of the AUC of FS in arterial plasma after administration of FS by various routes. The high intrinsic capability of the gut and liver to hydrolyze FS was reflected by E values which ranged from 69 to 91%. Since the gut is the first site after an oral dose, its contribution to the overall first-pass hydrolysis (greater than 75% of the absorbed dose) was estimated to be significantly greater than that of the liver (less than 25% of the absorbed dose). Concentrations of FS were similar in central arterial and venous plasma after a steady state arterial infusion of 14C-FS, indicating that the lung is apparently not a site of prodrug hydrolysis. This conclusion was consistent with the results of in vitro studies that indicated the following order of esterase activity: liver = kidney much greater than small intestine greater than blood, aorta, and lung. When data from in vitro studies were extrapolated to the in vivo situation, the blood itself was not a significant site for hydrolysis of FS in dogs. Based on the body clearance of FS (approximately 30 ml/min/kg) estimated after the intra-arterial route, roughly 50% of the systemic hydrolysis of the prodrug appears to occur at extrahepatic site(s), such as the kidney.

Angiotensin-Converting Enzyme Inhibitors↗
PubMedDate not supplied

Biotransformation of tipredane, a novel topical steroid, in mouse, rat, and human liver homogenates.

The in vitro biotransformation pathways of 3H-tipredane (3H-TP) were studied. 3H-TP, at concentrations of 1 and 250 microM, was incubated with the 10,000g supernatant fraction of the liver homogenates of mice, rats, and one human. The incubation mixtures were deproteinated with methanol and, after removal of methanol by evaporation, extracted with dichloromethane. The dichloromethane extracts were then fractionated by HPLC. 3H-TP was extensively biotransformed by the liver homogenates of the three species studied; 17 metabolites were isolated and characterized by their retention times on HPLC compared to those of the reference standards. Fourteen metabolites were identified using MS and, for some, NMR spectroscopy. Three major biotransformation pathways of TP were identified: 1) sulfoxidation, 2) elimination of the alkylthio groups, and 3) hydroxylation of the steroid nucleus. Combinations of these processes and subsequent reactions resulted in the formation of numerous metabolites whose biological activities were significantly less than that of TP. The separation of local anti-inflammatory activity from systemic side effects observed for TP in animals and humans is most probably due to its metabolic inactivation, primarily in the liver.

Administration, Topical↗
PubMedDate not supplied

The comparative metabolism and disposition of penfluridol-3H in the rat, rabbit, dog, and man.

Penfluridol, 1-[4,4-bis(4-fluorophenyl)butyl]-4-[4-chloro-3-(trifluoromethyl)phenyl]-4-piperidinol, was well absorbed by the rat, rabbit, dog, and man after single oral doses of drug in solution. Penfluridol and its metabolites were widely distributed in tissues of male rats and cleared slowly. The terminal plasma t 1/2 for penfluridol was greater than 40 hr for the rabbit, 227 hr for the dog, and 199 hr for man. Fecal excretion of total radioactivity predominated in the rat, rabbit, and dog whereas in man excretion was evenly divided between urine and feces. The major biotransformation pathways of penfluridol in the rat, rabbit, dog, and man were oxidative N-dealkylation followed by beta-oxidation, conjugation of penfluridol, and conjugation of the acidic metabolites.

Animals↗
PubMedDate not supplied

The metabolism of zomepirac sodium. I. Disposition in laboratory animals and man.

Zomepirac sodium (ZS) is an orally active, nonnarcotic, analgesic agent. The disposition and pharmacokinetics of zomepirac (Z) were studied in rats, mice, rabbits, hamsters, rhesus monkeys, and healthy human subjects. Z was rapidly and completely absorbed by all animal species and man. Dose-related linear increases in the area under the curve for plasma Z vs. time were noted after increasing po doses of ZS to mice (2.5--7.5 mg/kg), rats (0.5--10 mg/kg), and rhesus monkeys (5--40 mg/kg). Daily administration of ZS to rats (10 mg/kg/day for 10 days) caused no biologically significant changes in the pharmacokinetic profile for Z. Assessment of Z's absolute bioavailability in monkeys (10 mg/kg, iv vs. po) indicated that po doses of ZS were completely bioavailable (F = 1.12 +/- 0.40). Plasma clearance ranged from ca. 4.5 ml/min/kg for the female hamster, rhesus monkey, and man to as low as 0.30 ml/min/kg for rats, mice, and rabbits. Terminal elimination half-lives averaged 5.3--6.6 hr for mouse, 2.8--6.5 hr for rat, 2.5 hr for rabbit, 2.3 hr for hamster, 12.7--25.5 hr for rhesus monkey, and 4 hr for man. The major route of excretion for Z and its metabolites was via the kidneys for all animals and man with the balance appearing in feces. Biliary excretion was qualitatively observed in rhesus monkeys and quantitated in rats (23.6% of dose in 27 hr). Formation of the acyl glucuronide of Z was the major metabolic pathway in man and rhesus monkey, was substantial in the mouse, was very minor in the rat and rabbit, and was nonexistent in the hamster. Rat, mouse, and hamster hydroxylate the 4-methyl group on the pyrrole ring to give hydroxyzomepirac (a biologically inactive metabolite), a minor metabolite in man and nonexistent in the rhesus monkey. The rodents also cleave Z to form 4-chlorobenzoic acid and its conjugates, minor metabolites in man and rhesus monkey.

Absorption↗